Wnt signaling pathway inhibitors for treatments of disease

ABSTRACT

Compounds and compositions are provided as inhibitors of the Wnt/β-catenin pathway for the treatment of diseases that implicate the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase Application under 35 U.S.C. §371 of International Application PCT/US17/20224, filed Mar. 1, 2017which claims the benefit of priority to U.S. Provisional Application No.62/352,634, filed Jun. 21, 2016, U.S. Provisional Application No.62/301,882, filed Mar. 1, 2016, and U.S. Provisional Application No.62/301,863, filed Mar. 1, 2016, the entireties of which are incorporatedherein by reference.

FIELD OF THE INVENTION

The present invention relates generally to compounds that inhibit theWnt signaling pathway and more particularly, but not exclusively, tocompounds that inhibit the Wnt/β-catenin pathway for the treatment ofdiseases that implicate the Wnt/β-catenin pathway.

BACKGROUND OF THE INVENTION

A number of individuals are affected each year by diseases thatimplicate aberrant activity in Wnt signalling, which may result inabnormal levels of β-catenin. These diseases include metabolic diseasesand cancer, for example.

There is a need in the field for new and potent therapeutics thatinhibit the Wnt/β-catenin pathway as treatments for disease. The presentinvention meets those needs.

SUMMARY OF THE INVENTION

The present invention meets the needs in the field by providingcompounds and methods for the treatment of diseases that implicate theWnt/β-catenin signaling pathway.

In one aspect the compounds of the invention may include a compound offormula I:

wherein R₁ and R₂ each may independently represent a substituentselected from the group consisting of H and substituted or unsubstitutedalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl,alkoxy, carboxy, carbalkoxy, and carboxamido;

R₃ may represent a substituent selected from the group consisting ofsubstituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heterocycle, and heteroaryl;

n may represent an integer of 0 to 2, Z represents one or moresubstituted or unsubstituted alkyl substituents when n is 1 or 2;

X₁ may represent N or CR₄;

X₂ may represent N or CR₅;

X₃ may represent N or CR₆; R₄, R₅, and R₆ each may independentlyrepresent a substitutent selected from the group consisting of H, OH,NO₂, CN, halo, and substituted or unsubstituted alkyl, alkylcarbonyl,alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, amino,alkoxy, carboxy, carbalkoxy, carboxamido, sulfonyl, sulfonamido,sulfinyl, monoalkylaminosulfinyl, dialkylaminosulfinyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino,hydroxysulfonyloxy, alkoxysulfonyloxy, alkylsulfonyloxy,hydroxysulfonyl, alkoxysulfonyl, alkylsulfonylalkyl,monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl,monoalkylaminosulfinylalkyl, and dialkylaminosulfinylalkyl; where if X₁and X₂ represent CR₄ and CR₅, respectively, then R₄ and R₅ may be takentogether to form a substituted or unsubstituted m-membered cycloalkyl orheterocycle, wherein m may represent an integer of 5 to 7; or thepharmaceutically acceptable salts of said compounds.

In some embodiments, the compounds of formula I may include a compoundof Table 1 or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds of the invention may include acompound of formula II:

wherein R₇ may represent a substituent selected from the groupconsisting of H and substituted or unsubstituted alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, alkoxy, carboxy,carbalkoxy, and carboxamido;

R₈ may represent a substituent selected from the group consisting of H,OH, NO₂, CN, halo, and substituted or unsubstituted alkyl, alkenyl,alkynyl, aryl, amino, and alkoxy;

R₉, R₁₀, R₁₁, R₁₂, and R₁₃ each may independently represent asubstituent selected from the group consisting of H, OH, NO₂, CN, halo,and substituted or unsubstituted alkyl, alkylcarbonyl, alkenyl, alkynyl,cycloalkyl, aryl, heterocycle, heteroaryl, amino, alkoxy, carboxy,carbalkoxy, carboxamido, sulfonyl, sulfonamido, sulfinyl,monoalkylaminosulfinyl, dialkylaminosulfinyl, monoalkylaminosulfonyl,dialkylaminosulfonyl, alkylsulfonylamino, hydroxysulfonyloxy,alkoxysulfonyloxy, alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl,alkylsulfonylalkyl, monoalkylaminosulfonylalkyl,dialkylaminosulfonylalkyl, monoalkylaminosulfinylalkyl, anddialkylaminosulfinylalkyl;

X₄ may represent N or CR₁₄;

X₅ may represent N or CR₁₅; R₁₄ and R₁₅ each may independently representa substitutent selected from the group consisting of H, OH, NO₂, CN,halo, and substituted or unsubstituted alkyl, alkylcarbonyl, alkenyl,alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, amino, alkoxy,carboxy, carbalkoxy, carboxamido, sulfonyl, sulfonamido, sulfinyl,monoalkylaminosulfinyl, dialkylaminosulfinyl, monoalkylaminosulfonyl,dialkylaminosulfonyl, alkylsulfonylamino, hydroxysulfonyloxy,alkoxysulfonyloxy, alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl,alkylsulfonylalkyl, monoalkylaminosulfonylalkyl,dialkylaminosulfonylalkyl, monoalkylaminosulfinylalkyl, anddialkylaminosulfinylalkyl; and where if X₄ and X₅ are CR₁₄ and CR₁₅,respectively, then R₁₄ and R₁₅ may be taken together to form asubstituted or unsubstituted m-membered cycloalkyl or heterocycle,wherein m may be an integer of 5 to 7; or the pharmaceuticallyacceptable salts of said compound.

In some embodiments, the compounds of formula II may include a compoundof Table 2 or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds of the invention may include acompound of Table 3 or a pharmaceutically acceptable salt thereof. Insome embodiments, the compounds of the invention may include a compoundselected from the group consisting of YW1132, YW1114, YW1130, YW1134,YW1128, YW1159, YW1169, YW1149, YW1173, YW1170, YW1157, YW1181, YW1179,YW2013, YW2018, YW2020, YW1132, YW2035, YW2038, YW2044, YW2049, YW2065,and YW2052, and a pharmaceutically acceptable salt thereof. In someembodiments, the compound of the invention may include YW1149, YW2013,YW2065, or YW2044, or a pharmaceutically acceptable salt thereof. Insome embodiments, the compound of the invention may include YW1149,YW1128, or a pharmaceutically acceptable salt thereof.

In another aspect, the invention may include a method of treating adisease alleviated by inhibiting Wnt/β-catenin signaling in a patient inneed of said treatment.

In some embodiments, the disease may be a metabolic disease or cancer.

In some embodiments, the metabolic disease may be selected from thegroup consisting of type 2 diabetes, obesity, hyperlipidemia, and fattyliver disease. In some embodiments, the metabolic disease is type 2diabetes. In some embodiments, fatty liver disease may include alcoholicfatty liver disease (ALD) or non-alcoholic fatty liver disease (NAFLD).In some embodiments, NAFLD may include one or more of simple fatty liverdisease (steatosis), non-alcoholic steatohepatitis (NASH), and livercirrhosis. In certain embodiments, the metabolic disease may be NASH.

In some embodiments, the disease implicating the disease may be cancer.In some embodiments, the cancer may be selected from the groupconsisting of adrenocortical cancer, hepatocellular cancer,hepatoblastoma, malignant melanoma, ovarian cancer, Wilm's tumor,Barrett's esophageal cancer, prostate cancer, pancreatic cancer, bladdercancer, breast cancer, gastric cancer, head & neck cancer, lung cancer,mesothelioma, cervical cancer, uterine cancer, myeloid leukemia cancer,lymphoid leukemia cancer, pilometricoma cancer, medulloblastoma cancer,glioblastoma, and familial adenomatous polyposis. In some embodiments,the cancer may include colon cancer.

In some embodiments, the method may include administering atherapeutically effective amount of one or more compounds having theformula of formula I or the pharmaceutically acceptable salts of saidone or more compounds. In some embodiments, the method may includeadministering a therapeutically effective amount of one or morecompounds provided in Table 1 or a pharmaceutically acceptable salt ofsaid one or more compounds. In some embodiments, the methods may includeadministering a therapeutically effective amount of one or morecompounds having the formula of formula II or a pharmaceuticallyacceptable salt of said one or more compounds. In some embodiments, themethods may include administering a therapeutically effective amount ofone or more compounds provided in Table 2 or a pharmaceuticallyacceptable salt of said one or more compounds. In some embodiments, themethods of the invention may include administering a therapeuticallyeffective amount of one or more compounds provided in Table 3 or apharmaceutically acceptable salt of said one or more compounds. In someembodiments, the methods of the invention may include administering atherapeutically effective amount of one or more compounds selected fromthe group consisting of YW1132, YW1114, YW1130, YW1134, YW1128, YW1159,YW1169, YW1149, YW1173, YW1170, YW1157, YW1181, YW1179, YW2013, YW2018,YW2020, YW1132, YW2035, YW2038, YW2044, YW2049, YW2065, and YW2052, andthe pharmaceutically acceptable salts of said one or more compounds. Insome embodiments, the methods of the invention may include administeringa therapeutically effective amount of YW1149, YW2013, YW2065, or YW2044,or a pharmaceutically acceptable salt thereof. In some embodiments, themethods of the invention may include administering a therapeuticallyeffective amount of YW1149, YW1128, or a pharmaceutically acceptablesalt thereof.

In some embodiments, the compounds of the invention may includeinhibitors of Wnt signaling. In some embodiments, the compounds of theinvention may downregulate β-catenin by inhibiting Wnt signaling. Insome embodiments, the compounds of the invention may upregulate Axinprotein expression. In some embodiments, the compounds of the inventionmay downregulate c-Myc. In some embodiments, the compounds of theinvention may modulate the activity of one or more of casein kinase 1alpha (CK1α), protein kinase B (Akt/PKB), and glycogen synthase kinase 3(GSK3). In some embodiments, the compounds of the invention mayupregulate the activity of CK1α. In some embodiments, the compounds ofthe invention may inhibit one or more of Akt/PKB and GSK3.

In some embodiments, the compounds of the invention may suppress glucoseproduction. The compounds of the invention may suppress the expressionof glucose 6-phosphatase (G6P). In some embodiments, the compounds ofthe invention may, increase phosphorylation of 5′ adenosinemonophosphate-activated protein kinase (AMP kinase or AMPK).

In some embodiments of the invention, the compounds of the invention maytreat or alleviate symptoms of a metabolic disease, such as type 2diabetes. In some embodiments, the compounds of the invention mayimprove glucose tolerance in a patient in need thereof. In someembodiments, the compounds of the invention may reduce fasting glucoselevels in a patient in need thereof. In some embodiments, the compoundsof the invention may suppress gluconeogenesis in a patient in needthereof. In some embodiments, the compounds of the invention may reverseobesity and/or decrease weight gain in a patient in need thereof. Insome embodiments, the compounds of the invention may increase insulinsensitivity in a patient in need thereof.

In some embodiments, the methods of the invention may includeadministering (1) a therapeutically effective amount of one or more of acompound of formula I, II, Table 1, Table 2, Table 3, and thepharmaceutically acceptable salts thereof; and (2) a therapeuticallyeffective amount of an additional therapeutic agent. In someembodiments, the additional therapeutic agent may include one or more ofa RAF inhibitor, an MEK inhibitor, an ERK inhibitor, a VEGFR inhibitor,and an EGFR inhibitor. In some embodiments, the VEGFR inhibitor mayinclude one or more of Bevacizumab (AVASTIN), Aflibercept (ZALTRAP), andRegorafenib (STIVARGA). In some embodiments, the EGFR inhibitor mayinclude one or more of Cetuximab (ERBITUX), Panitumumab (VECTIBIX), andGefitinib. In some embodiments, the additional therapeutic agent mayinclude pyrvinium.

In some embodiments of the invention, the compounds of the invention maytreat or alleviate symptoms of a disease implicating the Wnt/β-cateninpathway, which may include metabolic disease or cancer.

In some embodiments, the disease implicating the Wnt/β-catenin pathwaymay be a metabolic disease, such as type 2 diabetes. In someembodiments, the compounds of the invention may improve glucosetolerance in a patient in need thereof. In some embodiments, thecompounds of the invention may reduce fasting glucose levels in apatient in need thereof. In some embodiments, the compounds of theinvention may suppress gluconeogenesis in a patient in need thereof. Insome embodiments, the compounds of the invention may reverse obesityand/or decrease weight gain in a patient in need thereof. In someembodiments, the compounds of the invention may increase insulinsensitivity in a patient in need thereof.

In some embodiments, the disease implicating the Wnt/β-catenin pathwaymay be cancer or a hyperoliferative disease. In some embodiments, thecancer or hyperproliferative disease may be one or more ofadrenocortical cancer, hepatocellular cancer, hepatoblastoma, malignantmelanoma, ovarian cancer, Wilm's tumor, Barrett's esophageal cancer,prostate cancer, pancreatic cancer, bladder cancer, breast cancer,gastric cancer, head & neck cancer, lung cancer, mesothelioma, cervicalcancer, uterine cancer, myeloid leukemia cancer, lymphoid leukemiacancer, pilometricoma cancer, medulloblastoma cancer, glioblastoma, andfamilial adenomatous polyposis. In some embodiments, the cancer orhyperproliferative disease may include colon cancer.

In another aspect, the invention includes a pharmaceutical compositionthat may include one or more compounds of formula I, or apharmaceutically acceptable salt thereof, and a physiologicallycompatible carrier medium. In some embodiments, the invention includes apharmaceutical composition that may include one or more compoundsdescribed in Table 1, or a pharmaceutically acceptable salt thereof, anda physiologically compatible carrier medium. In some embodiments, theinvention includes a pharmaceutical composition that may include one ormore compounds of formula II, or a pharmaceutically acceptable saltthereof, and a physiologically compatible carrier medium. In someembodiments, the invention includes a pharmaceutical composition thatmay include one or more compounds described in Table 2, or apharmaceutically acceptable salt thereof, and a physiologicallycompatible carrier medium. In some embodiments, the invention includes apharmaceutical composition that may include one or more compoundsdescribed in Table 3, or a pharmaceutically acceptable salt thereof, anda physiologically compatible carrier medium. In some embodiments, theinvention includes a pharmaceutical composition that may include one ormore of YW1132, YW1114, YW1130, YW1134, YW1128, YW1159, YW1169, YW1149,YW1173, YW1170, YW1157, YW1181, YW1179, YW2013, YW2018, YW2020, YW1132,YW2035, YW2038, YW2044, YW2049, YW2065, and YW2052, or apharmaceutically acceptable salt thereof, and a physiologicallycompatible carrier medium. In some embodiments, the invention includes apharmaceutical composition that may include YW1149, YW2013, YW2065, orYW2044, or a pharmaceutically acceptable salt thereof, and aphysiologically compatible carrier medium. In some embodiments, theinvention includes a pharmaceutical composition that may include YW1149,YW1128, or a pharmaceutically acceptable salt thereof, and aphysiologically compatible carrier medium.

In some embodiments, the compositions of the invention may include (1)one or more of a compound of formula I, II, Table 1, Table 2, Table 3,and the pharmaceutically acceptable salts thereof; (2) an additionaltherapeutic agent; and a physiologically compatible carrier medium. Insome embodiments, the additional therapeutic agent may include one ormore of a RAF inhibitor, an MEK inhibitor, an ERK inhibitor, a VEGFRinhibitor, and an EGFR inhibitor. In some embodiments, the VEGFRinhibitor may include one or more of Bevacizumab (AVASTIN), Aflibercept(ZALTRAP), and Regorafenib (STIVARGA). In some embodiments, the EGFRinhibitor may include one or more of Cetuximab (ERBITUX), Panitumumab(VECTIBIX), and Gefitinib. In some embodiments, the additionaltherapeutic agent may include pyrvinium.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing summary and the following detailed description of theexemplary embodiments of the present invention may be further understoodwhen read in conjunction with the appended drawings, in which:

FIG. 1 illustrates the results of a dual luciferase gene reporter assayfor Wnt/β-catenin signaling inhibition that compares the inhibitoryactivity of pyrvinium to YW1149.

FIGS. 2A and 2B illustrate the effects of pyrvinium treatment on bodyweight gain and glucose tolerance in mice. C57BL/6 mice (n=6/group) wereput either on high-fat (HF) or normal chow (NC) diet. Seven weeks afterthe start of the HF diet, the mice received either pyrvinium (Pyr)(initial 0.2 mg/kg/2 days and increased to 0.5 mg/kg/2 days from day 20)or vehicle (Veh) by I.P. for 5 weeks. Body weight monitoring during thestudy is shown in FIG. 2A. Intraperitoneal glucose tolerance test (GTT)is shown in FIG. 2B. GTT was conducted at the end of the study. *P<0.05compared to the other 3 groups.

FIG. 3 illustrates the effect of treatment of YW1149 or pyrvinium on theexpression of Wnt pathway proteins. HepG2 cells were treated by YW1149(vehicle, 0.1, 1 μM). HEK293 cells treated by pyrvinium (vehicle, 0.1,1, 10 μM).

FIGS. 4A to 4C illustrate the effects of YW1149 and pyrvinium on glucoseproduction (FIG. 4A), G6P expression (FIG. 4B), and AMPK phosphorylation(FIG. 4C) in HepG2 cells. In FIGS. 4A and 4B: 0.1 μM pyrvinium and 10 μMYW1149. *P<0.05; **P<0.01 compared to vehicle treatment.

FIGS. 5A and 5B illustrate the the metabolic stability of YW1149. S9fraction from mouse liver tissues (FIG. 5A) and mouse plasma samples(FIG. 5B) were mixed with YW1149 and incubated at 37 degrees,respectively. *P<0.05 as compared to time 0.

FIGS. 6A and 6B illustrate a pharmacokinetic study for YW1149 andpyrvinium in mice. Single intravenous (IV, tail vein) and oraladministration of YW1149 (10 mg/kg) (FIG. 6A) and pyrvinium pamoate (2mg/kg) (FIG. 6B) were dosed in 12-week old C57BL/6 mice, respectively.The mice that received IV pyrvinium died after thirty minutes.Representative data from each group is shown.

FIGS. 7A and 7B illustrate a comparison of cytotoxicity and mousetoxicity between YW1149 and pyrvinium. In FIG. 7A, the cytotoxicity ofYW1149 and pyrvinium was assessed using a colorimetric assay, CCK-8, inHEK293 cells. In FIG. 7B, a Kaplan-Meier survival analysis of the micewas performed where the mice received single intravenous (IV, tail vein)dosages of YW1149 (10 mg/kg) or pyrvinium pamoate (2 mg/kg). 12-week oldC57BL/6 mice were used (n=5 or 6 mice/group).

FIGS. 8A and 8B illustrate the effect of certain compounds of theinvention on cell proliferation and growth in SW480 cells at 10 μM (FIG.8A) and 50 μM (FIG. 8B).

FIG. 9 illustrates the inhibitory effect of certain compounds of theinvention on cell proliferation and growth in SW480 cells.

FIG. 10 describes the relationships between various cells lines andtheir sources.

FIG. 11 illustrates the cytoxic activity of certain compounds of theinvention in various cancer cells lines.

FIG. 12 illustrates the cytotoxic activity of certain compounds of theinvention on the micromolar scale in various cancer cell lines.

FIG. 13 illustrates the cytotoxic activity of YW2013 and YW2044 againstSW620 cells.

FIG. 14 illustrates the cytotoxic activity of YW2013 and YW2044 againstSW480 cells.

FIG. 15 illustrates the cytotoxic activity of YW2013 and YW2044 againstWiDr cells.

FIG. 16 illustrates the activity of YW2013 and YW2044 as inhibitors ofβ-catenin signaling in SW480 cells.

FIG. 17 illustrates the activity of YW2013 as an inhibitor of β-cateninsignaling in SW480 cells in a TOPflash/FOPFlash assay with and withoutLiCl.

FIG. 18 illustrates the activity of YW2013 and YW2044 as inhibitors ofβ-catenin signaling in SW620 cells.

FIG. 19 illustrates the effect of YW2013 on mRNA expression of Wntregulated genes in A549 cells.

FIG. 20 illustrates the effect of YW2013 on mRNA expression of Wntregulated genes in SW620 cells.

FIG. 21 illustrates the effect of YW2013 and YW2044 on mRNA expressionof Wnt regulated genes in SW620 cells.

FIG. 22 illustrates the effect of YW2013 on mRNA expression of Wntregulated genes in WiDr cells.

FIG. 23 illustrates the effect of YW2013 and YW2123 on Axin-2,β-catenin, and c-myc protein expression in SW480 cells.

FIG. 24 illustrates the effect of YW2044 on colony formation in HT-29cells.

FIG. 25 illustrates the effect of YW2013 on colony formation in SW480cells.

FIG. 26 illustrates the effect of YW2013 on colony formation in SW620cells.

FIGS. 27A and 27B illustrate the effect of YW2013 on cell cycle in SW620cells that are unsynchronized (FIG. 27A) and synchronized (FIG. 27B).

FIG. 28 illustrates the effect of YW2013 on cell cycle in SW620 cellsthat are unsynchronized.

FIG. 29 illustrates the effect of YW2013 on cell cycle in SW620 cellsthat are synchronized.

FIG. 30 illustrates the apoptotic effect of YW2013 on SW620 cells.

FIG. 31 illustrates the effect of YW2013 in combination with Gefitinibon cell colony formation in SW620 cells.

FIG. 32 illustrates the apopotic effect of YW2013 in combination withGefitinib on SW620 cells.

FIGS. 33A to 33D illustrate the effect of Wnt signaling inhibitor YW1128on hepatic lipid accumulation in mice fed with a high-fat diet. FIGS.33A and 33B illustrate liver histology (H&E staining) for those miceeuthanized at 11 weeks, which were given vehicle.

FIGS. 33C and 33D illustrate liver histology (H&E staining) for thosemice euthanized at 11 weeks, which were given YW1128.

FIGS. 34A and 34B illustrate the effect of Wnt signaling inhibitorYW1128 on glucose tolerance in mice fed with a high-fat diet. FIG. 34Aillustrates the glucose level for mice over 120 minutes post-injectionat week 0 of the study. FIG. 34B illustrates the glucose level for miceover 120 minutes post-injection at week 11 of the study. *P<0.05,**P<0.01 compared to the YW1128 group.

FIG. 35 illustrates the effect of Wnt signalling inhibitor YW1128 onbody weight gain in mice fed with a normal chow (NC) diet and mice fedwith a high-fat diet (HFD). *P<0.05 for the comparison betweenHFD-vehicle and the other three groups.

FIGS. 36A to 36D illustrate the effect of YW1128 on a high-fat diet(HFD)-induced steatosis. FIG. 36A illustrates representative liverhistology by H&E staining. FIG. 36B illustrates an intraperitonealglucose tolerance test (IPGTT) performed at the end of a study.

FIG. 36C illustrates body weight monitoring performed during thetreatment. FIG. 36D illustrates increased phosphorylation of AMPKα1 atthreonine 172 (T172) (p-AMPKα) in YW1128-treated livers as compared tovehicle-treated livers. CK1a did not show any significant change.*P<0.05, compared with the corresponding YW1128 group.

FIGS. 37A to 37C illustrate that YW2065 inhibited SW620 xenograft growthin nude mice. FIG. 37A illustrates tumor growth measured during thestudy every other day. FIG. 37B illustrates tumor weight that wasmeasured after mouse euthanization. FIG. 37C illustrates the change inmouse body weight during the study.

FIGS. 38A to 38D illustrate the effects of YW2065 treatment onmitochondrial function and morphology in SW480 cancer cells. FIG. 38Aillustrates that YW2065 reduced oxygen consumption rate (OCR). FIG. 38Billustrates ATP production estimated from the OCR measurement. FIG. 38Cillustrates how YW2065 (10 μM) caused short and punctuated mitochondriain SW480 cells after 4 hours of treatment. FIG. 38D illustrates howYW2065 increased ROS generation in SW480 cells as evaluated by stainingthe cells with DHE. DHE fluorescence intensity was measured by usingImageJ. ˜300 cells were counted in each treatment.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates generally to compounds, and methods ofusing such compounds, that may inhibit the Wnt/β-catenin signalingpathway. More specifically, the compounds of the invention arerepresented in formulas I and II, which may be used in treating diseasesthat implicate the Wnt/β-catenin signaling pathway.

The Wnt/β-catenin signaling pathway plays a pivotal role in cellproliferation and differentiation. Moreover, it regulates thetranscription of its target genes through the transcriptional factorβ-catenin. In the “off state” without Wnt ligands, β-catenin forms acytoplasmic “destruction complex” with adenomatous polyposis coli (APC)and Axin, which facilitiates the phosphorylation of β-catenin byglycogen synthase kinase 3 (GSK3) and casein kinase 1 (CK1) at theN-terminal residues Ser45, Thr41, Ser37, and Ser33. Phosphorylatedβ-catenin is recognized and ubiquitinated by the F-box β-transducinrepeat-containing protein (β-TrCP), and then degraded by the proteasome.On the other hand, the “on-state” of the pathway involves increasedpost-translational stability and thus accumulation of β-catenin, throughWnt-dependent degradation of Axin and inhibition of GSK3 by variousmechanisms. As the β-catenin level increases, it translocates to thenucleus where it binds to LEF/TCF such as TCF7L2 and activatesexpression of downstream genes. Increased expression of β-catenin andmalfunction of the Wnt-signaling pathway are implicated in a variety ofdiseases.

In one embodiment, the compounds of the invention may be used astreatments for metabolic disease in a patient in need thereof. As usedherein, the term “metabolic disease” may refer to diseases that involvea disruption to a patient's metabolic homeostasis, including, but notlimited to, type 2 diabetes, obesity, hyperlipidemia, and fatty liverdisease. In some embodiments, the metabolic disease described in theinvention may be type 2 diabetes. In some embodiments, fatty liverdisease may include alcoholic fatty liver disease (ALD) or non-alcoholicfatty liver disease (NAFLD). In some embodiments, NAFLD may include oneor more of simple fatty liver disease (steatosis), non-alcoholicsteatohepatitis (NASH), and liver cirrhosis. In certain embodiments, themetabolic disease may be NASH.

Research in different groups has identified an association between type2 diabetes risk and single nucleotide polymorphisms (SNPs) in TCF7L2, aneffector of the Wnt/β-catenin pathway. Similar genetic evidence has beenobtained for additional modulators of the Wnt signaling pathway,including WNT5B, WNT10B, and LRP6. Therefore, the Wnt/β-catenin pathwayhas emerged as a novel therapeutic target for treating disease,including metabolic disorders.

With respect to cancer, the Wnt pathway may be activated in a variety ofcancers including, for example, colon cancer, hepatocellular carcinoma,lung cancer, ovarian cancer, prostate cancer, pancreatic cancer, andleukemias such as CML, CLL and T-ALL. The activation is due toconstitutively active β-catenin, perhaps, without being limited to anyone theory, due to its stabilization by interacting factors orinhibition of the degradation pathway. Accordingly, the compounds andcompositions described herein may be used to treat these cancers inwhich the Wnt pathway is constitutively activated.

In some embodiments, the disease implicating the Wnt/β-catenin pathwaymay be cancer or a hyperoliferative disease. In some embodiments, thecancer or hyperproliferative disease may be one or more ofadrenocortical cancer, hepatocellular cancer, hepatoblastoma, malignantmelanoma, ovarian cancer, Wilm's tumor, Barrett's esophageal cancer,prostate cancer, pancreatic cancer, bladder cancer, breast cancer,gastric cancer, head & neck cancer, lung cancer, mesothelioma, cervicalcancer, uterine cancer, myeloid leukemia cancer, lymphoid leukemiacancer, pilometricoma cancer, medulloblastoma cancer, glioblastoma, andfamilial adenomatous polyposis. In some embodiments, the cancer orhyperproliferative disease may include colon cancer.

In some embodiments, cancers that may be treated by the compounds,compositions and methods described herein include, but are not limitedto, the following:

-   -   1) Breast cancers, including, for example ER+ breast cancer, ER−        breast cancer, her2− breast cancer, her2+ breast cancer, stromal        tumors such as fibroadenomas, phyllodes tumors, and sarcomas,        and epithelial tumors such as large duct papillomas; carcinomas        of the breast including in situ (noninvasive) carcinoma that        includes ductal carcinoma in situ (including Paget's disease)        and lobular carcinoma in situ, and invasive (infiltrating)        carcinoma including, but not limited to, invasive ductal        carcinoma, invasive lobular carcinoma, medullary carcinoma,        colloid (mucinous) carcinoma, tubular carcinoma, and invasive        papillary carcinoma; and miscellaneous malignant neoplasms.        Further examples of breast cancers can include luminal A, lumina        B, basal A, basal B, and triple negative breast cancer, which is        estrogen receptor negative (ER−), progesterone receptor        negative, and her2 negative (her2−). In some embodiments, the        breast cancer may have a high risk Oncotype score;    -   2) Cardiac cancers, including, for example sarcoma, e.g.,        angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma;        myxoma; rhabdomyoma; fibroma; lipoma and teratoma;    -   3) Lung cancers, including, for example, bronchogenic carcinoma,        e.g., squamous cell, undifferentiated small cell,        undifferentiated large cell, and adenocarcinoma; alveolar and        bronchiolar carcinoma; bronchial adenoma; sarcoma; lymphoma;        chondromatous hamartoma; and mesothelioma;    -   4) Gastrointestinal cancer, including, for example, cancers of        the esophagus, e.g., squamous cell carcinoma, adenocarcinoma,        leiomyosarcoma, and lymphoma; cancers of the stomach, e.g.,        carcinoma, lymphoma, and leiomyosarcoma; cancers of the        pancreas, e.g., ductal adenocarcinoma, insulinoma, glucagonoma,        gastrinoma, carcinoid tumors, and vipoma; cancers of the small        bowel, e.g., adenocarcinoma, lymphoma, carcinoid tumors,        Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma,        and fibroma; cancers of the large bowel, e.g., adenocarcinoma,        tubular adenoma, villous adenoma, hamartoma, and leiomyoma;    -   5) Genitourinary tract cancers, including, for example, cancers        of the kidney, e.g., adenocarcinoma, Wilm's tumor        (nephroblastoma), lymphoma, and leukemia; cancers of the bladder        and urethra, e.g., squamous cell carcinoma, transitional cell        carcinoma, and adenocarcinoma; cancers of the prostate, e.g.,        adenocarcinoma, and sarcoma; cancer of the testis, e.g.,        seminoma, teratoma, embryonal carcinoma, teratocarcinoma,        choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,        fibroadenoma, adenomatoid tumors, and lipoma;    -   6) Liver cancers, including, for example, hepatoma, e.g.,        hepatocellular carcinoma; cholangiocarcinoma; hepatoblastoma;        angiosarcoma; hepatocellular adenoma; and hemangioma;    -   7) Bone cancers, including, for example, osteogenic sarcoma        (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,        chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum        cell sarcoma), multiple myeloma, malignant giant cell tumor        chordoma, osteochrondroma (osteocartilaginous exostoses), benign        chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma        and giant cell tumors;    -   8) Nervous system cancers, including, for example, cancers of        the skull, e.g., osteoma, hemangioma, granuloma, xanthoma, and        osteitis deformans; cancers of the meninges, e.g., meningioma,        meningiosarcoma, and gliomatosis; cancers of the brain, e.g.,        astrocytoma, medulloblastoma, glioma, ependymoma, germinoma        (pinealoma), glioblastoma multiform, oligodendroglioma,        schwannoma, retinoblastoma, and congenital tumors; and cancers        of the spinal cord, e.g., neurofibroma, meningioma, glioma, and        sarcoma;    -   9) Gynecological cancers, including, for example, cancers of the        uterus, e.g., endometrial carcinoma; cancers of the cervix,        e.g., cervical carcinoma, and pre tumor cervical dysplasia;        cancers of the ovaries, e.g., ovarian carcinoma, including        serous cystadenocarcinoma, mucinous cystadenocarcinoma,        unclassified carcinoma, granulosa theca cell tumors, Sertoli        Leydig cell tumors, dysgerminoma, and malignant teratoma;        cancers of the vulva, e.g., squamous cell carcinoma,        intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and        melanoma; cancers of the vagina, e.g., clear cell carcinoma,        squamous cell carcinoma, botryoid sarcoma, and embryonal        rhabdomyosarcoma; and cancers of the fallopian tubes, e.g.,        carcinoma;    -   10) Hematologic cancers, including, for example, cancers of the        blood, e.g., acute myeloid leukemia, chronic myeloid leukemia,        acute lymphoblastic leukemia, chronic lymphocytic leukemia,        myeloproliferative diseases, multiple myeloma, and        myelodysplastic syndrome, Hodgkin's lymphoma, non Hodgkin's        lymphoma (malignant lymphoma) and Waldenström's        macroglobulinemia;    -   11) Skin cancers and skin disorders, including, for example,        malignant melanoma, basal cell carcinoma, squamous cell        carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma,        angioma, dermatofibroma, keloids, and psoriasis;    -   12) Adrenal gland cancers, including, for example,        neuroblastoma; and    -   13) Pancreatic cancer.

Cancers may be solid tumors that may or may not be metastatic. Cancersmay also occur, as in leukemia, as a diffuse tissue. Thus, the term“tumor cell,” as provided herein, includes a cell afflicted by any oneof the above identified disorders.

A method of treating cancer using a compound or composition as describedherein may be combined with existing methods of treating cancers, forexample by chemotherapy, irradiation, or surgery (e.g., oophorectomy).In some embodiments, a compound or composition can be administeredbefore, during, or after another anticancer agent, additionaltherapeutic agent, or treatment.

The compounds of the invention may include those described by formula I:

wherein R₁ and R₂ each may independently represent a substituentselected from the group consisting of H and substituted or unsubstitutedalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl,alkoxy, carboxy, carbalkoxy, and carboxamido;

R₃ may represent a substituent selected from the group consisting ofsubstituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heterocycle, and heteroaryl;

n may represent an integer of 0 to 2, Z represents one or moresubstituted or unsubstituted alkyl substituents when n is 1 or 2;

X₁ may represent N or CR₄;

X₂ may represent N or CR₅;

X₃ may represent N or CR₆; R₄, R₅, and R₆ each may independentlyrepresent a substitutent selected from the group consisting of H, OH,NO₂, CN, halo, and substituted or unsubstituted alkyl, alkylcarbonyl,alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, amino,alkoxy, carboxy, carbalkoxy, carboxamido, sulfonyl, sulfonamido,sulfinyl, monoalkylaminosulfinyl, dialkylaminosulfinyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino,hydroxysulfonyloxy, alkoxysulfonyloxy, alkylsulfonyloxy,hydroxysulfonyl, alkoxysulfonyl, alkylsulfonylalkyl,monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl,monoalkylaminosulfinylalkyl, and dialkylaminosulfinylalkyl; and where ifX₁ and X₂ represent CR₄ and CR₅, respectively, then R₄ and R₅ may betaken together to form a substituted or unsubstituted m-memberedcycloalkyl or heterocycle, wherein m may represent an integer of 5 to 7.

In some embodiments of formula I, n may represent 0 or 1. In otherembodiments, n represents 0.

In some embodiments of formula I, X₃ may represent CR₆, where R₆ may bealkyl (e.g., methyl, ethyl, n-propyl, i-propyl), halo (e.g., chloro,bromo), or substituted or unsubstituted amino (e.g., NMe₂).

In some embodiments of formula I, R₁ may represent substituted orunsubstituted aryl (e.g., phenyl, naphthyl) or heteroaryl (e.g.,quinolinyl, thiazolyl, isooxazolyl, benzithiazolyl, benzimidizolyl,isoquinolinyl, pyridinyl, pyrimidinyl, benzopyronyl).

In some embodiments of formula I, X₁ and X₂ may be N. In someembodiments, X₂ is N and X₃ is CR₆. In some embodiments, X₁ is CR₄ andX₂ is N.

In some embodiments of formula I, R₂ may be H.

In some embodiments of formula I, R₃ may be substituted or unsubstitutedphenyl.

In some embodiments of formula I, m may be an integer of 5 or 6.

In some embodiments, the compounds of the invention may include thosedescribed by formula II:

wherein R₇ may represent a substituent selected from the groupconsisting of H and substituted or unsubstituted alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, alkoxy, carboxy,carbalkoxy, and carboxamido;

R₈ may represent a substituent selected from the group consisting of H,OH, NO₂, CN, halo, and substituted or unsubstituted alkyl, alkenyl,alkynyl, aryl, amino, and alkoxy;

R₉, R₁₀, R₁₁, R₁₂, and R₁₃ each may independently represent asubstituent selected from the group consisting of H, OH, NO₂, CN, halo,and substituted or unsubstituted alkyl, alkylcarbonyl, alkenyl, alkynyl,cycloalkyl, aryl, heterocycle, heteroaryl, amino, alkoxy, carboxy,carbalkoxy, carboxamido, sulfonyl, sulfonamido, sulfinyl,monoalkylaminosulfinyl, dialkylaminosulfinyl, monoalkylaminosulfonyl,dialkylaminosulfonyl, alkylsulfonylamino, hydroxysulfonyloxy,alkoxysulfonyloxy, alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl,alkylsulfonylalkyl, monoalkylaminosulfonylalkyl,dialkylaminosulfonylalkyl, monoalkylaminosulfinylalkyl, anddialkylaminosulfinylalkyl;

X₄ may represent N or CR₁₄;

X₅ may represent N or CR₁₅; R₁₄ and R₁₅ each may independently representa substitutent selected from the group consisting of H, OH, NO₂, CN,halo, and substituted or unsubstituted alkyl, alkylcarbonyl, alkenyl,alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, amino, alkoxy,carboxy, carbalkoxy, carboxamido, sulfonyl, sulfonamido, sulfinyl,monoalkylaminosulfinyl, dialkylaminosulfinyl, monoalkylaminosulfonyl,dialkylaminosulfonyl, alkylsulfonylamino, hydroxysulfonyloxy,alkoxysulfonyloxy, alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl,alkylsulfonylalkyl, monoalkylaminosulfonylalkyl,dialkylaminosulfonylalkyl, monoalkylaminosulfinylalkyl, anddialkylaminosulfinylalkyl; and where if X₄ and X₅ are CR₁₄ and CR₁₅,respectively, then R₁₄ and R₁₅ may be taken together to form asubstituted or unsubstituted m-membered cycloalkyl or heterocycle,wherein m may be an integer of 5 to 7.

In some embodiments of formula II, R₇ may be substituted orunsubstituted aryl (e.g., phenyl, naphthyl) or heteroaryl (e.g.,quinolinyl, thiazolyl, isooxazolyl, benzithiazolyl, benzimidizolyl,isoquinolinyl, pyridinyl, pyrimidinyl, benzopyronyl).

In some embodiments of formula II, m may be an integer of 5 or 6.

In some embodiments of formula II, X₄ and X₅ may both be N.

In some embodiments of formula II, R₈ may be alkyl (e.g., methyl, ethyl,n-propyl, i-propyl), halo (e.g., chloro, bromo), or substituted orunsubstituted amino (e.g., NMe₂).

Regarding the compounds of the invention, which are encompassed withinformulas I and II, as used herein, the term “alkyl” denotes branched orunbranched hydrocarbon chains, having about 1 to 10 carbons, such as,methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, 2-methylpentyl, pentyl, hexyl, isohexyl, heptyl,4,4-dimethyl pentyl, octyl, 2,2,4-trimethylpentyl, and the like.“Substituted alkyl” includes an alkyl group optionally substituted withone or more functional groups which are attached commonly to suchchains, such as, hydroxy, halogen, mercapto or thio, cyano, alkylthio,carboxy, nitro, alkoxy, or optionally substituted, alkyl, amino,alkenyl, carboxamido, carbalkoxy, alkynyl, heterocyclyl, aryl,heteroaryl, and the like to form alkyl groups such as trifluoromethyl,3-hydroxyhexyl, 2-carboxypropyl, 2-fluoroethyl, carboxymethyl,cyanobutyl, phenethyl, benzyl, and the like.

The term “halogen” or “halo” as used herein alone or as part of anothergroup refers to chloro, bromo, fluoro, or iodo.

The term “alkoxy” refers to alkyl-O—, in which alkyl is as definedabove.

The term “alkylthio” refers to alkyl-S—, in which alkyl is as definedabove.

The term “alkylamino” refers to —NR′R″, in which R′ and R″ each mayindependently represent H, alkyl, or aryl, all as defined herein.

The term “alkylcarbonyl” refers to —C(═O)-alkyl, in which alkyl is asdefined above.

The term “carboxy” refers to the moiety —C(═O)OH.

The term “carbalkoxy” refers to the moiety —C(═O)—O-alkyl, in whichalkyl is as defined above.

The term “carboxamido” refers to the moiety —C(═O)—NR′R″, in which R′and R″, each may independently represent H, alkyl, or aryl, all asdefined herein.

The term “alkylsulfonyl” refers to the moiety —S(═O)₂-alkyl, in whichalkyl is as defined above.

The term “arylsulfonyl” refers to the moiety —S(═O)₂-aryl, in which arylis as defined herein. For example, arylsulfonyl may be —S(═O)₂-phenyl.

The term “arylsulfonyloxy” refers to the moiety —OS(═O)₂-alkyl, whereinalkyl is as defined above.

The term “amino(monoalkylamino-, dialkylamino-)sulfinyl” refers to themoiety —S(═O)NR′R″, in which R′ and R″ each may independently representH, alkyl, or aryl, all as defined herein.

The term “amino(monoalkylamino-, dialkylamino-)sulfonyl” refers to themoiety —S(═O)₂NR′R″, in which R′ and R″ each may independently representH, alkyl, or aryl, all as defined herein.

The term “alkylsulfonylamino” refers to the moiety —NHS(═O)₂-alkyl, inwhich alkyl is as previously defined.

The term “hydroxysulfonyloxy” refers to the moiety —OS(═O)₂OH.

The term “alkoxysulfonyloxy” refers to the moiety —OS(═O)₂O-alkyl, inwhich alkyl is as defined above.

The term “alkylsulfonyloxy” refers to the moiety —OS(═O)₂-alkyl, inwhich alkyl is as previously defined.

The term “hydroxysulfonyl” refers to the moiety —S(═O)₂OH.

The term “alkoxysulfonyl” refers to the moiety —S(═O)₂O-alkyl, whereinalkyl is as previously defined.

The term “alkylsulfonylalkyl” refers to the moiety -alkyl-S(═O)₂-alkyl,wherein each alkyl may be as previously defined.

The term “amino(monoalkylamino-, dialkylamino-)sulfonylakyl” refers tothe moiety -alkyl-S(═O)₂—NR′R″, wherein alkyl is as previously defined,and R′ and R″ each may independently represent H, alkyl, or aryl, all asdefined herein.

The term “amino(monoalkylamino-, dialkylamino-)sulfinylalkyl” refer tothe moieties -alkyl-S(═O)—NR′R″, wherein alkyl is as previously defined,and R′ and R″ each may independently represent H, alkyl, or aryl, all asdefined herein.

Unless otherwise indicated, the term “cycloalkyl” as employed hereinalone or as part of another group includes saturated or partiallyunsaturated (containing 1 or more double bonds) cyclic hydrocarbongroups containing 1 to 3 rings, including monocyclicalkyl, bicyclicalkyland tricyclicalkyl, containing a total of 3 to 20 carbons forming therings, preferably 3 to 10 carbons, forming the ring and which may befused to 1 or 2 aromatic rings as described for aryl, which includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclodecyl, cyclododecyl, and cyclohexenyl. “Substitutedcycloalkyl” includes a cycloalkyl group optionally substituted with 1 ormore substituents such as halogen, alkyl, substituted alkyl, alkoxy,hydroxy, aryl, substituted aryl, aryloxy, cycloalkyl, alkylamido,alkanoylamino, oxo, acyl, arylcarbonylamino, amino, nitro, cyano, thioland/or alkylthio and/or any of the substituents included in thedefinition of “substituted alkyl.”

Unless otherwise indicated, the term “alkenyl” as used herein by itselfor as part of another group refers to straight or branched chain of 2 to20 carbons, preferably 2 to 12 carbons, and more preferably 2 to 8carbons in the normal chain, which include one or more double bonds inthe normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl,4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl,4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl,4,8, 12-tetradecatrienyl, and the like. “Substituted alkenyl” includesan alkenyl group optionally substituted with one or more substituents,such as the substituents included above in the definition of“substitutedalkyl” and “substituted cycloalkyl.”

Unless otherwise indicated, the term “alkynyl” as used herein by itselfor as part of another group refers to straight or branched chain of 2 to20 carbons, preferably 2 to 12 carbons and more preferably 2 to 8carbons in the normal chain, which include one or more triple bonds inthe normal chain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl,3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl,3-octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl, 4-dodecynyl and the like.“Substituted alkynyl” includes an alkynyl group optionally substitutedwith one or more substituents, such as the substituents included abovein the definition of “substituted alkyl” and “substituted cycloalkyl.”

Unless otherwise indicated, the term “aryl” or “Ar” as employed hereinalone or as part of another group refers to monocyclic, bicyclic, and/orpolycyclic aromatic groups containing 6 to 10 carbons in the ringportion (such as phenyl or naphthyl including 1-naphthyl and 2-naphthyl)and may optionally include one to three additional rings fused to acarbocyclic ring or a heterocyclic ring, such as aryl, cycloalkyl,heteroaryl, or cycloheteroalkyl rings or substituted forms thereof.

“Substituted aryl” includes an aryl group optionally substituted withone or more functional groups, such as halo, alkyl, haloalkyl (e.g.,trifluoromethyl), alkoxy, haloalkoxy (e.g., difluoromethoxy), alkenyl,alkynyl, cycloalkyl-alkyl, cycloheteroalkyl, cycloheteroalkylalkyl,aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy,alkoxycarbonyl, alkylcarbonyl, arylcarbonyl, arylalkenyl,aminocarbonylaryl, arylthio, arylsulfinyl, arylazo, heteroarylalkyl,heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro,cyano, amino, substituted amino wherein the amino includes 1 or 2substituents (which are optionally substituted alkyl, aryl or any of theother substituents recited herein), thiol, alkylthio, arylthio,heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylaminocarbonyl,arylaminocarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy,alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl,arylsulfonylamino, or arylsulfonaminocarbonyl and/or any of the alkylsubstituents recited herein.

Unless otherwise indicated, the term “heteroaryl” as used herein aloneor as part of another group refers to a 5- to 7-membered aromatic ringwhich includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygen orsulfur and such rings fused to an aryl, cycloalkyl, heteroaryl orheterocycloalkyl ring (e.g. benzothiophene, indole, quinoline, thiazole,isooxazole, benzothiazole, benzimidizole, isoquinoline, pyridine,pyrimidine, benzopyrone, oxazole, thiazole, pyrazine), and includespossible N-oxides. “Substituted heteroaryl” includes a heteroaryl groupoptionally substituted with 1 to 4 substituents, such as thesubstituents included above in the definition of “substituted alkyl” and“substituted cycloalkyl.” Substituted heteroaryl also includes fusedheteroaryl groups which include, for example, quinoline, isoquinoline,indole, isoindole, carbazole, acridine, benzopyrene, benzopyrone,benzimidazole, benzofuran, isobenzofuran, phenanthroline, purine, andthe like.

Moreover, the terms “heterocyclo,” “heterocycle,” or “heterocyclicring,” as used herein, refer to an unsubstituted or substituted stable5- to 7-membered monocyclic ring system which may be saturated orunsaturated, and which consists of carbon atoms and from one to fourheteroatoms selected from N, O or S, and wherein the nitrogen and sulfurheteroatoms may optionally be oxidized, and the nitrogen heteroatom mayoptionally be quaternized. The heterocyclic ring may be attached at anyheteroatom or carbon atom which results in the creation of a stablestructure. Examples of such heterocyclic groups include, but are notlimited to, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl,oxopyrrolidinyl, oxoazepinyl, azepinyl, pyrrolyl, pyrrolidinyl,benzothiophene, chromone, benzopyrene, benzopyrone, furanyl, thienyl,pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl,isooxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl,isothiazolyl, thiadiazolyl, tetrahydropyranyl, thiamorpholinyl,thiamorpholinylsulfoxide, thiamorpholinylsulfone, and oxadiazolyl.

As used herein, the terms “optionally substituted” or “substituted” mayindicate that a chemical moiety referred to, for example, alkyl, aryl,and heteroaryl, may be unsubstituted or substituted with one or moregroups including, without limitation, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, arylalkyl, substituted arylalkyl, aryl,substituted aryl, heterocycle, substituted heterocycle, heteroaryl,substituted heteroaryl, hydroxyl, amino, substituted amino, alkoxy,substituted alkoxy, halogen, carboxy, nitro, carbalkoxy, substitutedcarbalkoxy, carboxamido, substituted carboxamido, alkylamino,substituted alkyl amino, monoalkylaminosulfinyl, substituted,monoalkylaminosulfinyl, dialkylaminosulfinyl, substituteddialkylaminosulfinyl, monoalkylaminosulfonyl, substitutedmonoalkylaminosulfonyl, dialkylaminosulfonyl, substituteddialkylaminosulfonyl, alkylsulfonylamino, substitutedalkylsulfonylamino, hydroxysulfonyloxy, alkoxysulfonyloxy, substitutedalkoxysulfonyloxy, alkylsulfonyloxy, substituted alkylsulfonyloxy,hydroxysulfonyl, alkoxysulfonyl, substituted alkoxysulfonyl,alkylsulfonylalkyl, substituted alkylsulfonylalkyl,monoalkylaminosulfonylalkyl, substituted monoalkylaminosulfonylalkyl,dialkylaminosulfonylalkyl, substituted dialkylaminosulfonylalkyl,monoalkylaminosulfinylalkyl, substituted monoalkylaminosulfinylalkyl,dialkylaminosulfinylalkyl, substituted dialkylaminosulfinylalkyl, andthe like. The chemical moieties of formulas I and II, above, that may beoptionally substituted include alkyl, alkenyl, alkynyl, cycloalkyl,arylalkyl, aryl, heterocycle, and heteroaryl, as described herein. Forexample, optionally substituted alkyl may include both propyl and2-chloro-propyl. Additionally, “optionally substituted” is alsoinclusive of embodiments where the named substituent or substituentshave multiple substituents rather than simply a single substituent. Forexample, optionally substituted aryl may include both phenyl and3-ethyl-5-methyl-6-bromo-phenyl.

The compounds of the invention may be administered as salts, which arealso within the scope of this invention. Pharmaceutically acceptable(i.e., non-toxic, physiologically compatible) salts are preferred. Ifthe compounds of the invention have, for example, at least one basiccenter, they can form acid addition salts. These are formed, forexample, with strong inorganic acids, such as mineral acids, for examplesulfuric acid, phosphoric acid or a hydrohalic acid, with strong organiccarboxylic acids, such as alkane carboxylic acids of 1 to 4 carbon atomswhich are unsubstituted or substituted, for example, by halogen, forexample acetic acid, such as saturated or unsaturated dicarboxylicacids, for example oxalic, malonic, succinic, maleic, fumaric, phthalicor terephthalic acid, such as hydroxycarboxylic acids, for exampleascorbic, glycolic, lactic, malic, tartaric or citric acid, such asamino acids, (for example aspartic or glutamic acid or lysine orarginine), or benzoic acid, or with organic sulfonic acids, such as(C₁-C₄) alkyl or arylsulfonic acids which are unsubstituted orsubstituted, for example by halogen, for example methyl- orparatoluene-sulfonic acid. Corresponding acid addition salts can also beformed having plural basic centers, if desired.

The compounds of the invention having at least one acid group (e.g.,carboxylic acid) can also form salts with suitable bases. Representativeexamples of such salts include metal salts, such as alkali metal oralkaline earth metal salts, for example sodium, potassium or magnesiumsalts, or salts with ammonia or an organic amine, such as morpholine,thiomorpholine, piperidine, pyrrolidine, a mono, di or trihydroxy loweralkylamine, for example ethyl, tert-butyl, diethyl, diisopropyl,triethyl, tributyl or dimethyl-propylamine, or a mono, di or trihydroxylower alkylamine, for example mono, di or triethanolamine. Correspondinginternal salts may also be formed.

For example, certain salts of the compounds described herein whichcontain a basic group include monohydrochloride, hydrogensulfate,methanesulfonate, phosphate or nitrate. Moreover, certain salts of thecompounds described herein which contain an acid group include sodium,potassium and magnesium salts and pharmaceutically acceptable organicamines.

All stereoisomers of the compounds of the invention, either in a mixtureor in pure or substantially pure form, are considered to be within thescope of this invention. The compounds of the invention may haveasymmetric centers at any of the carbon atoms including any one of thesubstituents. Consequently, compounds of the invention may exist inenantiomeric or diastereomeric forms or in mixtures thereof.Furthermore, where a stereocenter existing in a compound of theinvention is represented as a racemate, it is understood that thestereocenter may encompass the racemic mixture of R and S isomers, the Sisomers, and the R isomers. The processes for preparation of suchcompounds can utilize racemates, enantiomers, or diastereomers asstarting materials. When diastereomeric or enantiomeric products areprepared, they can be separated by conventional methods including,chromatographic, chiral HPLC, fractional crystallization, ordistillation. Some compounds of the present invention have groupsincluding alkenyls, iminyls, and the like, which may exist as entgegen(E) or zusammen (Z) conformations, in which case all geometric formsthereof, both E and Z, cis and trans, and mixtures thereof, are withinthe scope of the present invention. Accordingly, when such geometricisomeric products are prepared, they can be separated by conventionalmethods for example, chromatographic, HPLC, distillation orcrystallization

In some embodiments, the compounds of the invention may include thosecompounds of formula I that are set forth in Table 1, below:

TABLE 1 Compounds of Formula I Compound Identifiers Compound NameCompound Structure YW1109 (14) 2,5-Dimethyl-N-(pyridin-2-yl)-1-(p-tolyl)-1H-pyrrole-3- carboxamide

YW1117-2 (15) 2,5-Dimethyl-N-(pyrazin-2-yl)- 1-(p-tolyl)-1H-pyrrole-3-carboxamide

YW1114 (16) 2,5-Dimethyl-N-(4- phenylthiazol-2-yl)-1-(p-tolyl)-1H-pyrrole-3-carboxamide

YW1104 (17) N-Benzyl-2,5-dimethyl-1-(p- tolyl)-1H-pyrrole-3-carboxamide

YW1119 (20) 5-Methyl-N-(pyridin-2-yl)-1-(p- tolyl)-1H-1,2,3-triazole-4-carboxamide

YW1134 (21) 5-Methyl-N-(6-methylpyridin-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole- 4-carboxamide

YW1121 (25) 5-Methyl-N-(pyridin-2- ylmethyl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide

YW1123 (26) 5-Methyl-N-(2-methyl-4-oxo- 4H-chromen-7-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide

YW1124 (24) 5-Methyl-N-(3-methylisoxazol- 5-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide

YW1125 (22) N-(4,5-diphenylthiazol-2-yl)-5- methyl-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide

YW1126 (23) 5-Methyl-N-(1-methyl-1H- benzo[d]imidazol-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4- carboxamide

YW1127 (27) 5-Methyl-N-(quinolin-2-yl)-1- (p-tolyl)-1H-i,2,3-triazole-4-carboxamide

YW1128 (28) 5-Methyl-N-(quinolin-2-yl)-1- (o-tolyl)-1H-1,2,3-triazole-4-carboxamide

YW1130 (31) 5-Methyl-N-(naphthalen-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4- carboxamide

YW1132 (29) N-(benzo[d]thiazol-2-yl)-5- methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide

YW1183 (30) 5-Methyl-N-(4-phenylthiazol-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole- 4-carboxamide

YW1170 (42) 1-(2,3-Dimethylphenyl)-5- methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide

YW1179 (32) 1-(2,4-Dimethylphenyl)-5- methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide

YW1173 (44) 1-(3-Chlorophenyl)-5-methyl-N- (quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide

YW1159 (33) 1-(2-Fluorophenyl)-5-methyl-N- (quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide

YW1169 (36) 1-(2-Bromophenyl)-5-methyl-N- (quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide

YW1157 (34) 1-(2-Cyanophenyl)-5-methyl-N- (quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide

YW1149 (35) 1-(2-Methoxyphenyl)-5-methyl- N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide

YW1171 (41) 1-(4-Fluoro-2-nitrophenyl)-5- methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide

YW1181 (39) 1-(2-Acetylphenyl)-5-methyl-N- (quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide

YW1182 (40) 1-(2-Carbamoylphenyl)-5- methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide

YW1180 (38) 1-([1,1′-biphenyl]-2-yl)-5- methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide

YW1155 (37) 5-Methyl-1-(2- morpholinophenyl)-N-(quinolin-2-yl)-1H-1,2,3-triazole-4- carboxamide

YW1151 (43) 5-Methyl-1-(naphthalen-1-yl)-N- (quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide

YW2020 (46) 1-(2-fluorophenyl)-5-isopropyl- N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide

YW2018 (45) 5-Ethyl-1-(2-fluorophenyl)-N- (quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide

YW2013 (132) 5-Methyl-N-(quinolin-2-yl)-1- (o-tolyl)-1H-pyrazole-4-carboxamide

YW2035 (133) 1-(2-Fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4- carboxamide

YW2065 (134) 1-(2-Bromophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4- carboxamide

YW6001 (166) 2,5-Dimethyl-N-(quinolin-2-yl)- 1-(o-tolyl)-1H-imidazole-4-carboxamide

YW6002 (167) 1-(2-Fluorophenyl)-2,5- dimethyl-N-(quinolin-2-yl)-1H-imidazole-4-carboxamide

YW6003 (168) 1-(2-Bromophenyl)-2,5- dimethyl-N-(quinolin-2-yl)-1H-imidazole-4-carboxamide

YW6004 (169) 2,5-Dimethyl-1-phenyl-N- (quinolin-2-yl)-1H-imidazole-4-carboxamide

YW2038 (135) 1-(2-Chlorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4- carboxamide

YW2044 (136) 1-(2-Ethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4- carboxamide

YW2048 (137) 1-(2,6-dimethylphenyl)-5- methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW2049 (138) 1-(Tert-butyl)-5-methyl-N- (quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW2046 (139) 1-(2,5-dimethylphenyl)-5- methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW2039 (140) 1-(2,4-difluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole- 4-carboxamide

YW2036 (141) 5-methyl-1-phenyl-N-(quinolin- 2-yl)-1H-pyrazole-4-carboxamide

YW2070 (142) 1-cyclohexyl-5-methyl-N- (quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW2052 (143) 5-methyl-1-(1-phenylethyl)-N-(quinolin-2-yl)-1H-pyrazole-4- carboxamide

YW2056 (144) 5-methyl-N-(quinolin-2-yl)-1- (2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide

YW2055 (145) 5-methyl-1-(3-methylpyridin-2- yl)-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW2068 (146) 1-(3-chloro-2-fluorophenyl)-5- methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW2074 (147) 1-(2,6-difluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole- 4-carboxamide

YW2076 (148) 1-(2-bromo-6-fluorophenyl)-5- methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW2106 (149) 5-methyl-1-phenyl-N-(quinolin- 2-yl)-1H-pyrazole-3-carboxamide

YW2107 (150) 5-methyl-N-(quinolin-2-yl)-1-(o- tolyl)-1H-pyrazole-3-carboxamide

YW2108 (151) 1-(2-ethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-3- carboxamide

YW2111 (152) 1-phenyl-N-(quinolin-2-yl)- 1,4,5,6-tetrahydrocyclopenta[c]pyrazole- 3-carboxamide

YW2122 (153) 1-phenyl-N-(quinolin-2-yl)- 4,5,6,7-tetrahydro-1H-indazole-3-carboxamide

YW21172 (154) 3,5-dimethyl-1-phenyl-N- (quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW2120 (155) 1-(2,5-dimethylphenyl)-3,5- dimethyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW2123 (156) 1-(2-bromophenyl)-3,5- dimethyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW2126 (157) 5-ethyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW2125 (158) 5-isopropyl-1-phenyl-N- (quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW2137 (159) 5-chloro-1-phenyl-N-(quinolin- 2-yl)-1H-pyrazole-4-carboxamide

YW2136 (160) 5-bromo-1-phenyl-N-(quinolin- 2-yl)-1H-pyrazole-4-carboxamide

YW2147 (161) 5-(dimethylamino)-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4- carboxamide

YW2142 (162) 1-(2-ethylphenyl)-5-methyl-N-(naphthalen-2-yl)-1H-pyrazole- 4-carboxamide

YW2144 (163) 1-(2-ethylphenyl)-N- (isoquinolin-3-yl)-5-methyl-1H-pyrazole-4-carboxamide

YW2143 (164) 1-(2-ethylphenyl)-5-methyl-N-(quinolin-3-yl)-1H-pyrazole-4- carboxamide

YW2146 (165) 1-(2-ethylphenyl)-5-methyl-N- (6-methylpyridin-2-yl)-1H-pyrazole-4-carboxamide

YA1061 N-(6-bromoquinolin-2-yl)-5- methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide

YA1065 5-methyl-N-(6- (morpholinomethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole- 4-carboxamide

YA1073 5-methyl-N-(6-((4- methylpiperazin-1-yl)methyl)quinolin-2-yl)-1-(o- tolyl)-1H-1,2,3-triazole-4- carboxamide

YA1081 5-methyl-N-(6-(pyrrolidin-1- ylmethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4- carboxamide

YA1083 N-(6- ((diethylamino)methyl)quinolin-2-yl)-5-methyl-1-(o-tolyl)-1H- 1,2,3-triazole-4-carboxamide

YA1093 5-methyl-N-(6-(piperidin-1- ylmethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4- carboxamide

YA1095 tert-butyl 4-((2-(5-methyl-1-(o- tolyl)-1H-1,2,3-triazole-4-carboxamido)quinolin-6- yl)methyl)piperazine-1- carboxylate

YA1097 N-(6- ((dimethylamino)methyl) quinolin-2-yl)-5-methyl-1-(o-tolyl)-1H- 1,2,3-triazole-4-carboxamide

YA1099 5-methyl-N-(6- (thiomorpholinomethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3- triazole-4-carboxamide

YA1105 5-methyl-N-(6-((4- morpholinopiperidin-1-yl)methyl)quinolin-2-yl)-1-(o- tolyl)-1H-1,2,3-triazole-4- carboxamide

YA1109 5-methyl-N-(6-((4-(4- methylpiperazin-1-yl)piperidin-1-yl)methyl)quinolin-2-yl)-1-(o- tolyl)-1H-1,2,3-triazole-4- carboxamide

In some embodiments, the compounds of the invention may include thosecompounds of formula II set forth in Table 2, below:

TABLE 2 Compounds of Formula II Compound Identifiers Compound NameCompound Structure YW1109 (14) 2,5-Dimethyl-N-(pyridin-2-yl)-1-(p-tolyl)-1H-pyrrole- 3-carboxamide

YW1117-2 (15) 2,5-Dimethyl-N-(pyrazin-2- yl)-1-(p-tolyl)-1H-pyrrole-3-carboxamide

YW1114 (16) 2,5-Dimethyl-N-(4- phenylthiazol-2-yl)-1-(p-tolyl)-1H-pyrrole-3- carboxamide

YW1104 (17) N-Benzyl-2,5-dimethyl-1- (p-tolyl)-1H-pyrrole-3- carboxamide

YW1119 (20) 5-Methyl-N-(pyridin-2-yl)- 1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide

YW1134 (21) 5-Methyl-N-(6- methylpyridin-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4- carboxamide

YW1121 (25) 5-Methyl-N-(pyridin-2- ylmethyl)-1-(p-tolyl)-1H-1,2,3-triazole-4- carboxamide

YW1123 (26) 5-Methyl-N-(2-methyl-4- oxo-4H-chromen-7-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4- carboxamide

YW1124 (24) 5-Methyl-N-(3- methylisoxazol-5-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4- carboxamide

YW1125 (22) N-(4,5-diphenylthiazol-2- yl)-5-methyl-1-(p-tolyl)-1H-1,2,3-triazole-4- carboxamide

YW1126 (23) 5-Methyl-N-(1-methyl-1H- benzo[d]imidazol-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole- 4-carboxamide

YW1127 (27) 5-Methyl-N-(quinolin-2-yl)- 1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide

YW1128 (28) 5-Methyl-N-(quinolin-2-yl)- 1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide

YW1130 (31) 5-Methyl-N-(naphthalen-2- yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide

YW1132 (29) N-(benzo[d]thiazol-2-yl)-5- methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide

YW1183 (30) 5-Methyl-N-(4- phenylthiazol-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4- carboxamide

YW1170 (42) 1-(2,3-Dimethylphenyl)-5- methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4- carboxamide

YW1179 (32) 1-(2,4-Dimethylphenyl)-5- methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4- carboxamide

YW1173 (44) 1-(3-Chlorophenyl)-5- methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4- carboxamide

YW1159 (33) 1-(2-Fluorophenyl)-5- methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4- carboxamide

YW1169 (36) 1-(2-Bromophenyl)-5- methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4- carboxamide

YW1157 (34) 1-(2-Cyanophenyl)-5- methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4- carboxamide

YW1149 (35) 1-(2-Methoxyphenyl)-5- methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4- carboxamide

YW1171 (41) 1-(4-Fluoro-2-nitrophenyl)- 5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4- carboxamide

YW1181 (39) 1-(2-Acetylphenyl)-5- methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4- carboxamide

YW1182 (40) 1-(2-Carbamoylphenyl)-5- methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4- carboxamide

YW1180 (38) 1-([1,1′-biphenyl1-2-yl)-5- methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4- carboxamide

YW1155 (37) 5-Methyl-1-(2- morpholinophenyl)-N-(quinolin-2-yl)-1H-1,2,3- triazole-4-carboxamide

YW1151 (43) 5-Methyl-1-(naphthalen-1- yl)-N-(quinolin-2-yl)-1H-1,2,3-triazole-4- carboxamide

YW2020 (46) 1-(2-fluorophenyl)-5- isopropyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4- carboxamide

YW2018 (45) 5-Ethyl-1-(2-fluorophenyl)- N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide

YW2013 (132) 5-Methyl-N-(quinolin-2-yl)- 1-(o-tolyl)-1H-pyrazole-4-carboxamide

YW2035 (133) 1-(2-Fluorophenyl)-5- methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW2065 (134) 1-(2-Bromophenyl)-5- methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW6001 (166) 2,5-Dimethyl-N-(quinolin- 2-yl)-1-(o-tolyl)-1H-imidazole-4-carboxamide

YW6002 (167) 1-(2-Fluorophenyl)-2,5- dimethyl-N-(quinolin-2-yl)-1H-imidazole-4- carboxamide

YW6003 (168) 1-(2-Bromophenyl)-2,5- dimethyl-N-(quinolin-2-yl)-1H-imidazole-4- carboxamide

YW6004 (169) 2,5-Dimethyl-1-phenyl-N- (quinolin-2-yl)-1H-imidazole-4-carboxamide

YW2038 (135) 1-(2-Chlorophenyl)-5- methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW2044 (136) 1-(2-Ethylphenyl)-5-methyl- N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW2048 (137) 1-(2,6-dimethylphenyl)-5- methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW2046 (139) 1-(2,5-dimethylphenyl)-5- methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW2039 (140) 1-(2,4-difluorophenyl)-5- methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW2036 (141) 5-methyl-1-phenyl-N- (quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW2055 (145) 5-methyl-1-(3- methylpyridin-2-yl)-N- (quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW2068 (146) 1-(3-chloro-2- fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H- pyrazole-4-carboxamide

YW2074 (147) 1-(2,6-difluorophenyl)-5- methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW2076 (148) 1-(2-bromo-6- fluorophenyl)-5-methyl-N- (quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW21172 (154) 3,5-dimethyl-1-phenyl-N- (quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW2120 (155) 1-(2,5-dimethylphenyl)-3,5- dimethyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW2023 (156) 1-(2-bromophenyl)-3,5- dimethyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW2126 (157) 5-ethyl-1-phenyl-N- (quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW2125 (158) 5-isopropyl-1-phenyl-N- (quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW2137 (159) 5-chloro-1-phenyl-N- (quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW2136 (160) 5-bromo-1-phenyl-N- (quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW2147 (161) 5-(dimethylamino)-1- phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide

YW2142 (162) 1-(2-ethylphenyl)-5-methyl- N-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide

YW2144 (163) 1-(2-ethylphenyl)-N- (isoquinolin-3-yl)-5-methyl-1H-pyrazole-4-carboxamide

YW2143 (164) 1-(2-ethylphenyl)-5-methyl- N-(quinolin-3-yl)-1H-pyrazole-4-carboxamide

YW2146 (165) 1-(2-ethylphenyl)-5-methyl- N-(6-methylpyridin-2-yl)-1H-pyrazole-4-carboxamide

YA1061 N-(6-bromoquinolin-2-yl)- 5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4- carboxamide

YA1065 5-methyl-N-(6- (morpholinomethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3- triazole-4-carboxamide

YA1073 5-methyl-N-(6-((4- methylpiperazin-1- yl)methyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole- 4-carboxamide

YA1081 5-methyl-N-(6-(pyrrolidin- 1-ylmethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole- 4-carboxamide

YA1083 N-(6- ((diethylamino)methyl) quinolin-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4- carboxamide

YA1093 5-methyl-N-(6-(piperidin-1- ylmethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole- 4-carboxamide

YA1095 tert-butyl 4-((2-(5-methyl-1- (o-tolyl)-1H-1,2,3-triazole-4-carboxamido)quinolin-6- yl)methyl)piperazine-1- carboxylate

YA1097 N-(6- ((dimethylamino)methyl) quinolin-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4- carboxamide

YA1099 5-methyl-N-(6- (thiomorpholinomethyl)quinolin-2-yl)-1-(o-tolyl)-1H- 1,2,3-triazole-4- carboxamide

YA1105 5-methyl-N-(6-((4- morpholinopiperidin-1-yl)methyl)quinolin-2-yl)-1- (o-tolyl)-1H-1,2,3-triazole- 4-carboxamide

YA1109 5-methyl-N-(6-((4-(4- methylpiperazin-1- yl)piperidin-1-yl)methyl)quinolin-2-yl)-1- (o-tolyl)-1H-1,2,3-triazole- 4-carboxamide

In some embodiments, the compounds of the invention may include thecompounds of Table 3.

In some embodiments, the compounds of the invention may include thosehaving the Wnt/β-catenin signaling inhibition activity set forth inTable 3, below:

TABLE 3 Compounds of Formula I with associated Wnt/β-catenin inhibitoryactivity (RLU % = Relative Light Units in reporter gene assays; SD =Standard Deviation). At 1 μM concentration Compound RLU % SD IC₅₀ YW11324.9 2 34 nM YW1104 92.9 20.3 49 μM YW1121 92.1 4 ND YW1125 55.1 9.9 NDYW1114 34.6 3.9 379 nM YW1117-2 112.6 10 ND YW1123 87.6 9.7 ND YW113019.7 3.2 471 nM YW1134 79.5 2 273 nM YW1124 121.3 13.4 48 μM YW1119106.1 17.1 ND YW1127 56.4 2 ND YW1109 79.8 3.8 ND YW1128 3.7 0.8 7.7 nMYW1155 99.8 4.8 ND YW1159 1.4 0.1 6.5 nM YW1169 3.2 1.7 10 nM YW115179.3 6.4 4 μM YW1149 5 0.3 88 nM YW1173 26.3 1.3 731 nM YW1170 17.8 1.7567 nM YW1157 6.5 0.6 76 nM YW1171 77.8 3.2 5 μM YW1180 104.5 8.7 52 μMYW1182 89.9 1.8 >100 μM YW1183 90.8 5.2 22 μM YW1181 18.1 0.8 814 nMYW1179 10.6 0.8 130 nM YW2013 1.9 0.4 9.6 nM YW2018 2.3 0.9 47 nM YW202017.7 4.3 177 nM

In some embodiments, the compounds of the invention may include one ormore compounds selected from the group consisting of YW1132, YW1114,YW1130, YW1134, YW1128, YW1159, YW1169, YW1149, YW1173, YW1170, YW1157,YW1181, YW1179, YW2013, YW2018, YW2020, YW1132, YW2035, YW2038, YW2044,YW2049, YW2065, and YW2052. In some embodiments, the compound of theinvention may be YW1149, YW2013, YW2065, and YW2044. In someembodiments, the compounds of the invention may include one or morecompounds selected from the group consisting of YW1132, YW1114, YW1130,YW1134, YW1128, YW1159, YW1169, YW1149, YW1173, YW1170, YW1157, YW1181,YW1179, YW2013, YW2018, and YW2020. In some embodiments, the compound ofthe invention may be YW1149 or YW1128.

The compounds of the invention may be used as part of a therapy ormethodology in treating a variety of diseases or conditions thatimplicate the Wnt/β-catenin pathway.

Specifically, the compounds of the invention may be used for treating ordelaying the progression of a disorder or disease that may be alleviatedby inhibiting the Wnt/β-catenin pathway, in a patient in need of suchtreatment, by administering a therapeutically effective amount of one ormore compounds of formulas I or II, as set forth herein.

In some embodiments, the compounds and compositions provided herein maybe used as inhibitors of one or more members of the Wnt pathway,including one or more Wnt proteins, and thus can be used to treat avariety of disorders and diseases in which aberrant Wnt signaling may beimplicated, such as cancer and other diseases associated with abnormalangiogenesis, cellular proliferation, and cell cycling. Accordingly, thecompounds and compositions provided herein can be used to treat cancer,to reduce or inhibit angiogenesis, to reduce or inhibit cellularproliferation and correct a genetic disorder due to mutations in Wntsignaling components.

In some embodiments, the cancer may be one or more of adrenocorticalcancer, hepatocellular cancer, hepatoblastoma, malignant melanoma,ovarian cancer, Wilm's tumor, Barrett's esophageal cancer, prostatecancer, pancreatic cancer, bladder cancer, breast cancer, gastriccancer, head & neck cancer, lung cancer, mesothelioma, cervical cancer,uterine cancer, myeloid leukemia cancer, lymphoid leukemia cancer,pilometricoma cancer, medulloblastoma cancer, glioblastoma, and familialadenomatous polyposis. In some embodiments, the cancer orhyperproliferative disease may include colon cancer.

Non-limiting examples of diseases which may be treated with thecompounds and compositions provided herein include a variety of cancers,diabetic retinopathy, neovascular glaucoma, rheumatoid arthritis,psoriasis, mycotic and viral infections, osteochondrodysplasia,Alzheimer's disease, osteoarthritis, polyposis coli,osteoporosis-pseudoglioma syndrome, familial exudativevitreoretinopathy, retinal angiogenesis, early coronary disease,tetra-amelia syndrome, Müllerian-duct regression and virilization,SERKAL syndrome, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzelphocomelia syndrome, odonto-onycho-dermal dysplasia, split-hand/footmalformation, caudal duplication syndrome, tooth agenesis, Wilms tumor,skeletal dysplasia, focal dermal hypoplasia, autosomal recessiveanonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome,fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willisyndrome, Beckwith-Wiedemann Syndrome and Rett syndrome.

In some embodiments, the methods of the invention may be used in thetreatment of metabolic disease, including, without limitation, type 2diabetes, obesity, hyperlipidemia, or fatty liver disease. In certainembodiments, the methods of the invention may be used in the treatmentof type 2 diabetes. In some embodiments, fatty liver disease may includealcoholic fatty liver disease (ALD) or non-alcoholic fatty liver disease(NAFLD). In some embodiments, NAFLD may include one or more of simplefatty liver disease (steatosis), non-alcoholic steatohepatitis (NASH),and liver cirrhosis. In certain embodiments, the methods of theinvention may be used in the treatment of NASH.

As used herein, the terms “administer,” “administration” or“administering” refer to (1) providing, giving, dosing, and/orprescribing by either a health practitioner or his authorized agent orunder his or her direction according to the disclosure; and/or (2)putting into, taking or consuming by the mammal, according to thedisclosure.

As used herein, the terms “treat,” “treatment,” and/or “treating” mayrefer to the management of a disease, disorder, or pathologicalcondition (e.g., cancer or metabolic disease) with the intent to cure,ameliorate, stabilize, and/or control the disease, disorder, orpathological condition. Regarding control of the disease, disorder, orpathological condition more specifically, “control” may include theabsence of disease progression, as assessed by the response to themethods recited herein, where such response may be complete (e.g.,placing the disease in remission) or partial (e.g., lessening orameliorating any symptoms associated with the disease). As used herein,the terms “prevent,” “preventing,” and/or “prevention” may refer toreducing the risk of developing a disease, disorder, or pathologicalcondition (e.g., cancer or metabolic disorder).

In some embodiments, the methods of the invention may include themodulation of protein activity, regulation, and/or expression. As usedherein, the terms “modulate” and “modulation” refer to a change inbiological activity for a biological molecule (e.g., a protein, gene,peptide, antibody, and the like), where such change may relate to anincrease in biological activity (e.g., increased activity, activation,expression, upregulation, and/or increased expression) or decrease inbiological activity (e.g., decreased activity, suppression,deactivation, downregulation, and/or decreased expression) for thebiological molecule.

As described herein, in some embodiments, the compounds used in themethods of the invention may inhibit Wnt signaling, which may result ina reduction of β-catenin. Indeed, in some embodiments, the compoundsused in the methods of the invention may inhibit Wnt signaling bydownregulating β-catenin levels. In some embodiments, the compounds ofthe invention may upregulate Axin protein expression. In someembodiments, the compounds of the invention may downregulate c-Myc. Insome embodiments, the compounds of the invention may modulate theactivity of one or more of casein kinase 1 alpha (CK1α), protein kinaseB (Akt/PKB), and glycogen synthase kinase 3 (GSK3). In some embodiments,the compounds of the invention may upregulate the activity of caseinkinase 1 alpha (CK1α). In some embodiments, the compounds of theinvention may downregulate the activity of one or more of Akt/PKB andGSK3. In some embodiments, the compounds of the invention may suppressthe expression of glucose 6-phosphatase (G6P). In some embodiments, thecompounds of the invention may increase phosphorylation of 5′ adenosinemonophosphate-activated protein kinase (AMP kinase or AMPK).

In some embodiments of the invention, the methods described herein mayinclude the treatment of certain symptoms of diseases that implicate theWnt/β-catenin signaling pathway.

For example, the methods of the invention may include treatments forsymptoms of cancer or metabolic diseases. In some embodiments, themethods of the invention may include treatments for symptoms of type 2diabetes.

In some embodiments, the compounds of the invention may suppress glucoseproduction. Furthermore, in some embodiments, the compounds of theinvention may improve glucose tolerance in a patient in need thereof. Insome embodiments, the compounds of the invention may reduce fastingglucose levels in a patient in need thereof. In some embodiments, thecompounds of the invention may suppress gluconeogenesis in a patient inneed thereof. In some embodiments, the compounds of the invention mayreverse obesity and/or decrease weight gain in a patient in needthereof. In some embodiments, the compounds of the invention mayincrease insulin sensitivity in a patient in need thereof.

In some embodiments, the methods may include the co-administration of acompound of the invention with an additional therapeutic agent. The term“co-administering” as used herein means a process whereby thecombination of a compound of the invention and at least one additionaltherapeutic agent is administered to the same patient. The compound ofthe invention and additional therapeutic may be administeredsimultaneously, at essentially the same time, or sequentially. Ifadministration takes place sequentially, the compound of the inventionmay be administered before or after a given additional therapeutic agentor treatment. The compound of the invention and additional therapeuticagent or treatment need not be administered by means of the same vehicleor physiologically compatible carrier medium. The compound of theinvention and the additional therapeutic agent may be administered oneor more times and the number of administrations of each component of thecombination may be the same or different. In addition, the compound ofthe invention and additional therapeutic agent or treatment need not beadministered at the same site.

In some embodiments, the methods of the invention may includeadministering (1) a therapeutically effective amount of one or more of acompound of formula I, II, Table 1, Table 2, Table 3, and thepharmaceutically acceptable salts thereof; and (2) a therapeuticallyeffective amount of an additional therapeutic agent. In someembodiments, the additional therapeutic agent may include one or more ofa RAF inhibitor, an MEK inhibitor, an ERK inhibitor, a VEGFR inhibitor,and an EGFR inhibitor. In some embodiments, the VEGFR inhibitor mayinclude one or more of Bevacizumab (AVASTIN), Aflibercept (ZALTRAP), andRegorafenib (STIVARGA). In some embodiments, the EGFR inhibitor mayinclude one or more of Cetuximab (ERBITUX), Panitumumab (VECTIBIX), andGefitinib. In some embodiments, the additional therapeutic agent mayinclude pyrvinium.

Furthermore, the described methods of treatment may normally includemedical follow-up to determine the therapeutic or prophylactic effectbrought about in the subject undergoing treatment with the compound(s)and/or composition(s) described herein.

Molecular modeling and computer-based modeling may be used in accordancewith the invention to both understand the protein targets of thetherapeutic agents described herein or to direct drug design in thepreparation of analogs. Data reflecting the effect of compounds of theinvention on protein binding, for example, or other resulting in vitroor in vivo activity data, may be used to develop a pharmacophore andpharmacophore model. As used herein, the term “pharmacophore” refers tothe ensemble of steric and electronic features that are necessary toensure the optimal supramolecular interactions with a specificbiological target structure and to trigger, activate, block, inhibit ormodulate the biological target's biological activity, as the case maybe. See, IUPAC, Pure and Applied Chemistry (1998) 70: 1129-1143.

As used herein, the term “pharmacophore model” refers to arepresentation of points in a defined coordinate system wherein a pointcorresponds to a position or other characteristic of an atom or chemicalmoiety in a bound conformation of a ligand and/or an interactingpolypeptide, protein, or ordered water. An ordered water is anobservable water in a model derived from structural determination of apolypeptide or protein. A pharmacophore model can include, for example,atoms of a bound conformation of a ligand, or portion thereof. Apharmacophore model can include both the bound conformations of aligand, or portion thereof, and one or more atoms that interact with theligand and are from a bound polypeptide or protein. Thus, in addition togeometric characteristics of a bound conformation of a ligand, apharmacophore model can indicate other characteristics including, forexample, charge or hydrophobicity of an atom or chemical moiety. Apharmacophore model can incorporate internal interactions within thebound conformation of a ligand or interactions between a boundconformation of a ligand and a polypeptide, protein, or other receptorincluding, for example, van der Waals interactions, hydrogen bonds ionicbonds, and hydrophobic interactions. A pharmacophore model can bederived from 2 or more bound conformations of a ligand.

Turning to the administration of therapeutics, the compounds of theinvention may be administered as described herein, or in a form fromwhich the active agent can be derived, such as a prodrug. A “prodrug” isa derivative of a compound described herein, the pharmacologic action ofwhich results from the conversion by chemical or metabolic processes invivo to the active compound. Prodrugs include compounds wherein an aminoacid residue, or a polypeptide chain of two or more (e.g., two, three orfour) amino acid residues is covalently joined through an amide or esterbond to a free amino, hydroxyl or carboxylic acid group of formulas Iand II. The amino acid residues include but are not limited to the 20naturally occurring amino acids commonly designated by one or threeletter symbols but also include, for example, 4-hydroxyproline,hydroxylysine, desmosine, isodesmosine, 3-methylhistidine, beta-alanine,gamma-aminobutyric acid, citrulline, homocysteine, homoserine, omithineand methionine sulfone. Additional types of prodrugs are alsoencompassed. For instance, free carboxyl groups can be derivatized asamides or alkyl esters. Prodrug esters as employed herein includesesters and carbonates formed by reacting one or more hydroxyls ofcompounds of the method of the invention with alkyl, alkoxy, or arylsubstituted acylating agents employing procedures known to those skilledin the art to generate acetates, pivalates, methylcarbonates, benzoatesand the like. As further examples, free hydroxyl groups may bederivatized using groups including but not limited to hemisuccinates,phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 115. Carbamate prodrugs of hydroxyl and amino groupsare also included, as are carbonate prodrugs, sulfonate prodrugs,sulfonate esters and sulfate esters of hydroxyl groups. Free amines canalso be derivatized to amides, sulfonamides or phosphonamides. All ofthe stated prodrug moieties may incorporate groups including but notlimited to ether, amine and carboxylic acid functionalities. Moreover,any compound that can be converted in vivo to provide the bioactiveagent (e.g., a compound of formula I) is a prodrug within the scope ofthe invention. Various forms of prodrugs are well known in the art. Acomprehensive description of pro drugs and prodrug derivatives aredescribed in: (a) The Practice of Medicinal Chemistry, Camille G.Wermuth et al., (Academic Press, 1996); (b) Design of Prodrugs, editedby H. Bundgaard, (Elsevier, 1985); (c) A Textbook of Drug Design andDevelopment, P. Krogsgaard-Larson and H. Bundgaard, eds., (HarwoodAcademic Publishers, 1991).

In general, prodrugs may be designed to improve the penetration of adrug across biological membranes in order to obtain improved drugabsorption, to prolong duration of action of a drug (slow release of theparent drug from a prodrug, decreased first-pass metabolism of thedrug), to target the drug action (e.g. organ or tumor-targeting,lymphocyte targeting), to modify or improve aqueous solubility of a drug(e.g., i.v. preparations and eyedrops), to improve topical drug delivery(e.g. dermal and ocular drug delivery), to improve thechemical/enzymatic stability of a drug, or to decrease off-target drugeffects, and more generally in order to improve the therapeutic efficacyof the compounds utilized in the invention.

A compound used in practicing any method of the invention may beadministered in an amount sufficient to induce the desired therapeuticeffect in the recipient thereof. Thus the term “therapeuticallyeffective amount” as used herein refers to an amount of a compound ofthe invention that is sufficient to treat a disease in accordance withthe invention by administration of one or more of the compounds offormulas I and/or II or a prodrug thereof. Preferably, thetherapeutically effective amount refers to the amount appropriate toinhibit the Wnt/β-catenin pathway. In addition, the term therapeuticallyeffective amount may include the amount of a compound necessary, forexample, to bring about a detectable therapeutic, preventative, orameliorative effect in a patient having a disease as set forth herein.The effect may include, for example, the reduction, prevention,amelioration, or stabilization of symptoms or conditions associated witha disease as described herein.

The compound(s) described herein may also be administered at a dose inrange from about 0.01 mg to about 200 mg/kg of body weight per day. Adose of from about 0.1 to 100 mg/kg, or from about 1 to 50 mg/kg per dayin one or more applications per day may be effective to produce thedesired result. By way of example, a suitable dose for oraladministration may be in the range of 1-50 mg/kg of body weight per day,whereas a dose for intravenous administration may be in the range of1-10 mg/kg of body weight per day.

Of course, as those skilled in the art will appreciate, the dosageactually administered will depend upon the condition being treated, theage, health and weight of the recipient, the type of concurrenttreatment, if any, and the frequency of treatment. Moreover, theeffective dosage amount may be determined by one skilled in the art onthe basis of routine empirical activity testing to measure thebioactivity of the compound(s) in a bioassay, and thus establish theappropriate dosage to be administered.

The compounds used in certain methods of the invention may typically beadministered from 1-4 times a day, so as to deliver the above-mentioneddaily dosage. However, the exact regimen for administration of thecompounds described herein will necessarily be dependent on the needs ofthe individual subject being treated, the type of treatment administeredand the judgment of the attending medical specialist. As used herein,the term “subject” or “patient” includes both humans and animals.

In general, the compounds used in the methods of the invention can beadministered in pure form or, as described herein, with physiologicallycompatible and/or acceptable carrier mediums, using any acceptable routeknown in the art, either alone or in combination with one or more othertherapeutic agents. Thus, the compound(s) and/or composition(s) of theinvention can be administered orally, parenterally, such as byintravenous or intraarterial infusion, intramuscular, intraperitoneal,intrathecal or subcutaneous injection, by liposome-mediated delivery,rectally, vaginally, by inhalation or insufflation, transdermally or byotic delivery.

The orally administered dosage unit may be in the form of tablets,caplets, dragees, pills, semisolids, soft or hard gelatin capsules,aqueous or oily solutions, emulsions, suspensions or syrups. Suitabledosage forms for parenteral administration include injectable solutionsor suspensions, suppositories, powder formulations, such asmicrocrystals or aerosol spray. The active agents of the invention mayalso be incorporated into a conventional transdermal delivery system.

As used herein, the expression “physiologically compatible carriermedium” (or “physiologically acceptable carrier medium” and the like)includes any and all solvents, diluents, or other liquid vehicles,dispersions or suspension aids, surface agent agents, isotonic agents,thickening or emulsifying agents, preservatives, solid binders,lubricants, fillers and the like as suited for the particular dosageform desired. Remington: The Science and Practice of Pharmacy, 20thedition, A. R. Genaro et al., Part 5, Pharmaceutical Manufacturing, pp.669-1015 (Lippincott Williams & Wilkins, Baltimore, Md./Philadelphia,Pa.) (2000) discloses various carriers used in formulatingpharmaceutical compositions and known techniques for the preparationthereof. Except insofar as any conventional pharmaceutical carriermedium is incompatible with the compounds of the present invention, suchas by producing an undesirable biological effect or otherwiseinteracting in an deleterious manner with any other component(s) of aformulation comprising such compounds or agents, its use is contemplatedto be within the scope of this invention.

For the production of solid dosage forms, including hard and softcapsules, the agents of the invention may be mixed with pharmaceuticallyinert, inorganic or organic excipients, such as lactose, sucrose,glucose, gelatine, malt, silica gel, starch or derivatives thereof,talc, stearic acid or its salts, dried skim milk, vegetable, petroleum,animal or synthetic oils, wax, fat, polyols, and the like. For theproduction of liquid solutions, emulsions or suspensions or syrups onemay use excipients such as water, alcohols, aqueous saline, aqueousdextrose, polyols, glycerine, lipids, phospholipids, cyclodextrins,vegetable, petroleum, animal or synthetic oils. For suppositories onemay use excipients, such as vegetable, petroleum, animal or syntheticoils, wax, fat and polyols. For aerosol formulations, one may usecompressed gases suitable for this purpose, such as oxygen, nitrogen andcarbon dioxide. Pharmaceutical compositions or formulations may alsocontain one or more additives including, without limitation,preservatives, stabilizers, e.g., UV stabilizers, emulsifiers,sweeteners, salts to adjust the osmotic pressure, buffers, coatingmaterials and antioxidants.

The invention further includes controlled-release, sustained release, orextended-release therapeutic dosage forms for administration of thecompounds of the invention, which involves incorporation of thecompounds into a suitable delivery system in the formation of certaincompositions. This dosage form controls release of the compound(s) insuch a manner that an effective concentration of the compound(s) in thebloodstream may be maintained over an extended period of time, with theconcentration in the blood remaining relatively constant, to improvetherapeutic results and/or minimize side effects. Additionally, acontrolled-release system would provide minimum peak to troughfluctuations in blood plasma levels of the compound.

In pharmaceutical compositions used in practicing the methods of theinvention more particularly, the specified compound(s) may be present inan amount of at least 0.5 and generally not more than 95% by weight,based on the total weight of the composition, including carrier mediumand/or supplemental active agent(s), if any. In some embodiments, theproportion of compound(s) varies between about 30-90% by weight of thecomposition.

In some embodiments, the compositions of the invention may include (1)one or more of a compound of formula I, II, Table 1, Table 2, Table 3,and the pharmaceutically acceptable salts thereof; (2) an additionaltherapeutic agent; and a physiologically compatible carrier medium. Insome embodiments, the additional therapeutic agent may include one ormore of a RAF inhibitor, an MEK inhibitor, an ERK inhibitor, a VEGFRinhibitor, and an EGFR inhibitor. In some embodiments, the VEGFRinhibitor may include one or more of Bevacizumab (AVASTIN), Aflibercept(ZALTRAP), and Regorafenib (STIVARGA). In some embodiments, the EGFRinhibitor may include one or more of Cetuximab (ERBITUX), Panitumumab(VECTIBIX) Gefitinib. In some embodiments, the additional therapeuticagent may include pyrvinium.

The following examples describe the invention in further detail. Theseexamples are provided for illustrative purposes only, and should in noway be considered as limiting the invention.

EXAMPLES Example 1: Development of New Inhibitors for Wnt SignalingPathway

Pyrvinium (Scheme 1) is an FDA approved anti-helminthic drug for thetreatment of pinworm infection. Recently lines of experimental evidencehave shown that pyrvinium is an inhibitor for the Wnt/β-cateninsignaling pathway that works by direct binding and activating of CK1α.Although pyrvinium showed promising activity in regulating the Wntsignaling pathway, its further clinical application was prohibited dueto major limitations of this compound. First, the inhibitory potency ofpyrvinium for the Wnt signaling pathway is modest. In addition,pyrvinium adopts various salt forms that are permanently charged, whichled to low bioavailability. Furthermore, the alkene linker of pyrviniummakes the dimethyl pyrrole fragment electron rich, which impairs thechemical stability of the pyrrole moiety.

In the on-going program in developing novel Wnt signaling inhibitors forvarious diseases such as cancer, diabetes, and other metabolicdisorders, it is hypothesized that molecules that mimic the chemicalstructure of pyrvinium, while with improved potency and bioavailability,can be novel candidates as therapeutics to target the Wnt signalingpathway.

A variety of compounds were prepared as Wnt signaling inhibitors. Thesecompounds, as shown below, were subsequently tested in a dual-luciferaseassay to measure Wnt/β-catenin pathway inhibition using a TCF/LEFresponsive reporter construct similar to that described in the field(see Thome et al, 2010).

In this assay, HEK293 cells were transiently transfected with fireflyluciferase plasmid containing the latter construct and constitutivelyactive renilla luciferase expression plasmids as control. Lithiumchloride (LiCl), which has been previously established as an activatorof the Wnt/β-catenin pathway through its direct and indirect effects onGSK3β was used for pathway activation. The inhibition of theWnt/β-catenin pathway by a compound may be determined after itsincubation with cells for 24 hours. As a point of comparison, whenpyrvinium is tested in the foregoing assay at 1 μM, the remaining Wntsignaling activity (or RLU %) was 29.1% with a standard deviation (SD)of 3.5%. The 50% of inhibition (IC₅₀) was calculated with a series ofpyrvinium concentrations to be at 294 μM of pyrvinium.

Scheme 2 describes the preparation of pyrrole-based derivatives 14-17.The synthesis started from the FeCl₃-catalyzed reaction of 10 and4-Toluidine 11 to generate the pyrrole-3-ester 12 followed by thehydrolysis of the ester to afford pyrrole-3-carboxylic acid 13. Couplingof the acid 13 with various amines yielded the final products 14-17 bythe employment of PyCIU as coupling reagent in moderate to good yields.

The access to trizaole-based compounds 20-45 was described in Scheme 3.Starting with the diazotization of the appropriate aniline, followed bythe addition of sodium azide and cyclization with β-ketone ester in theEtONa/EtOH medium gave the key intermediate trizaole-3-carboxylic acid19. Finally, the PyCIU-mediated coupling reaction of 19 with variousaromatic amines in dichloroethane solvent allowed access to targetcompounds 20-45 in moderate to good yields.

TABLE 4 Effect of Quinoline Modifications in Pyrrole-based Scaffold onInhibitory Activities against LiCl-mediated WNT Signaling Pathway.

IC₅₀ (nM) or remaining Compound R activity at 1 μM Pyrvinium — 293 14

79.8% @ 1 μM 15

 112% @ 1 μM 16

379 17

  93% @ 1 μM

TABLE 5 Optimization of the replacement of quinolone in thetrizaole-based scaffold.

IC₅₀ (nM) or remaining Compound Ar activity at 1 μM 20

100% @ 1 μM 21

   273 22

   1000 23

ND 24

  48000 25

 >1000 26

 >1000

TABLE 6 Optimization of the phenyl substituents in the trizaole-basedscaffold.

IC₅₀ (nM) or remaining Compound R activity at 1 μM 27 4-CH₃ 56.4 ± 2.0 @1 μM 28 2-CH₃      6.3 32 2-CH₃, 4-CH₃     130   33 2-F      6.5 34 2-CN    76   35 2-OCH₃     88   36 2-Br     10   37 2-morpholine  >1000   382-Ph    52000   39 2-COCH3     814   40 2-CONH2 >100000   41 2-NO2, 4-F   5000   42 2-CH3, 3-CH3     567   43 1-naphthyl    4000   44 3-Cl    731  

TABLE 7 Optimization of the ortho-position on the phenyl substituentwhile varying the amide substituents on the triazole-based scaffold.

Com- IC₅₀ pound Ar R1 R2 (nM) 29

CH₃ CH₃   34 30

CH₃ CH₃ 22000 31

CH₃ CH₃  471 45

CH₂CH₃ F   47 46

CH(CH₃)₂ F  177

EXPERIMENTALS

Chemistry.

All chemicals were obtained from commercial suppliers and used withoutfurther purification. Analytical thin layer chromatography wasvisualized by ultraviolet light at 256 nM. ¹H NMR spectra were recordedon a Varian (400 MHz) spectrometer. Data are presented as follows:chemical shift (in ppm on the δ scale relative to δ=0.00 ppm for theprotons in tetramethylsilane (TMS)), integration, multiplicity(s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad),coupling constant (J/Hz). ¹³C NMR spectra were recorded at 100 MHz, andall chemical shifts values are reported in ppm on the δ scale with aninternal reference of δ 77.0 or 39.0 for CDCl3 or DMSO-d₆, respectively.The purities of title compounds were determined by analytic HPLC,performed on an Agilent 1100 instrument and a reverse-phase column(Waters XTerrra RP18, 5 μM, 4.6×250 mm). All compounds were eluted with60% acetonitrile/40 water (containing 0.1% TFA) over 20 mins with adetection at 260 nM and a flow rate at 1.0 mL/min. All tested compoundswere >95% pure.

Ethyl 2,5-dimethyl-1-(p-tolyl)-1H-pyrrole-3-carboxylate (12)

To a solution of ethyl 2-acetylpent-4-ynoate (1.68 g, 10 mmol),4-methylaniline (1.07 g, 10 mmol) in toluene (20 mL) was added FeCl₃(168 mg, 1 mmol). The mixture was stirred at 80° C. overnight. Aftercooling to room temperature, to the mixture was added ethyl acetate (50mL). The resulting mixture was washed with water, dried over Na₂SO₄ andconcentrated. The residue was purified by column chromatography(Hexane/AcOEt, v/v=4/1) to give the title compound as oil (2.18 g, 85%).

2,5-Dimethyl-1-(p-tolyl)-1H-pyrrole-3-carboxylic acid (13)

To a solution of 12 (2.57 g, 10 mmol) in MeOH (20 mL) was added KOH (2.8g, 50 mmol). The mixture was stirred under reflux overnight. The solventwas removed under vacuum and the residue was dissolved in water, washedwith diethyl ether. The aqueous layer was acidified to pH=1-2 using 1MHCl to give the title compound 13 as a white solid (1.6 g, 70%). ¹H-NMR(400 MHz, DMSO-d₆) δ 11.58 (s, 1H), 7.32-7.30 (d, J=8 Hz, 2H), 7.14-7.12(d, J=8 Hz, 2H), 6.17 (s, 1H), 2.35 (s, 3H), 2.14 (s, 3H), 1.87 (s, 3H);¹³C-NMR (100 MHz, DMSO-d₆) δ 166.7, 138.5, 135.5, 134.9, 130.4, 128.2,122.7, 111.7, 108.0, 21.1, 12.9, 12.5.

2,5-dimethyl-N-(pyridin-2-yl)-1-(p-tolyl)-1H-pyrrole-3-carboxamide (14)

To a solution of 13 (274 mg, 1.2 mmol), 2-aminopyridine (94 mg, 1.0mmol) in dichloroethane (5 mL) was added1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate (398mg, 1.2 mmol) and DIPEA (516 mg, 4 mmol). The mixture was stirred at 80°C. overnight. The solvent was removed under vacuum and the residue wasre-dissolved in ethyl acetate (15 mL). The resulting solution was washedwith water and brine, dried over Na₂SO₄ and concentrated. The crudeproduct was purified by column chromatography (Hexane/AcOEt, v/v=2/1) togive the targeted compound as a white solid (152 mg, 50%). ¹H-NMR (400MHz, CDCl₃) δ 8.37-8.35 (d, J=8 Hz, 1H), 8.27-8.24 (m, 2H), 7.71-7.69(t, J=8 Hz, 1H), 7.30-7.28 (d, J=8 Hz, 2H), 7.08-7.06 (d, J=8 Hz, 2H),7.00-6.97 (t, J=5.6 Hz, 1H), 6.24 (s, 1H), 2.43 (s, 3H), 2.36 (s, 3H),2.00 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ 164.1, 152.2, 147.6, 138.6138.2, 134.8, 130.2, 130.0, 129.2, 127.8, 127.7, 118.8, 113.8, 104.4,21.2, 12.7, 12.4. HRMS (ESI): m/z [M+H]⁺ calcd for C₁₉H₂₀N₃O 306.1606,found 306.1602. HPLC: t_(R)=7.02 min, 98.0%.

2,5-Dimethyl-N-(pyrazin-2-yl)-1-(p-tolyl)-1H-pyrrole-3-carboxamide (15)

Compound 15 was prepared from pyrazinamine (95 mg, 1.0 mmol) in a mannersimilar to that described for compound 14. (Purification: silica gelcolumn chromatography (hexane/AcOEt, v/v=4/1 to 2/1)). White solid.Yield: 146 mg, 48%. ¹H-NMR (400 MHz, CDCl₃) δ 9.72 (s, 1H), 8.31 (s,1H), 8.23 (s, 1H), 8.16 (s, 1H) 7.32-7.30 (d, J=8.0 Hz, 2H), 7.09-7.07(d, J=8.0 Hz, 2H), 6.26 (s, 1H), 2.45 (s, 3H), 2.37 (s, 3H), 2.01 (s,3H); ¹³C-NMR (100 MHz, CDCl₃) δ 163.6, 149.0, 141.8, 139.2, 138.8,137.1, 136.6, 134.7, 130.1, 129.5, 127.8, 112.9, 104.4, 21.2, 12.7,12.5. HRMS (ESI): m/z [M+H]⁺ calcd for C₁₈H₁₉N₄O 307.1559, found307.1557. HPLC: t_(R)=6.42 min, 99.6%.

2,5-dimethyl-N-(4-phenylthiazol-2-yl)-1-(p-tolyl)-1H-pyrrole-3-carboxamide(16)

Compound 16 was prepared from 4-phenylthiazol-2-amine (176 mg, 1.0 mmol)in a manner similar to that described for compound 14. (Purification:silica gel column chromatography (hexane/AcOEt, v/v=4/1 to 2/1)). Whitesolid. Yield: 263 mg, 68%. ¹H-NMR (400 MHz, CDCl₃) δ 9.60 (s, 1H),7.86-7.84 (d, J=8.0 Hz, 2H), 7.46-7.42 (t, J=8.0 Hz, 2H), 7.37-7.30 (m,3H), 7.11 (s, 1H), 7.10-7.08 (d, J=8.0 Hz, 2H), 6.34 (s, 1H), 2.45 (s,3H), 2.40 (s, 3H), 2.02 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ 162.7,158.6, 149.6, 138.8, 137.0, 134.6, 134.6, 130.1, 129.6, 128.7, 127.8,127.7, 126.0, 111.7, 107.2, 104.2, 21.2, 12.7, 12.5. HRMS (ESI): m/z[M+H]⁺ calcd for C₂₃H₂₂N₃OS 388.1484, found 388.1557. HPLC: t_(R)=12.18min, 99.0%.

N-benzyl-2,5-dimethyl-1-(p-tolyl)-1H-pyrrole-3-carboxamide (17)

Compound 17 was prepared from benzylamine (107 mg, 1.0 mmol) in a mannersimilar to that described for compound 14. (Purification: silica gelcolumn chromatography (hexane/AcOEt, v/v=4/1 to 2/1)). White solid.Yield: 241 mg, 76%. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.19 (s, 1H), 7.36-7.28(m, 6H), 7.22 (m, 1H), 7.17-7.15 (d, J=8.0 Hz, 2H), 6.41 (s, 1H), 2.39(s, 3H), 2.20 (s, 3H), 1.93 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ 165.9,139.2, 138.4, 135.0, 134.3, 129.9, 128.7, 128.6, 127.9, 127.7, 127.2,113.6, 104.1, 43.2, 21.2, 12.7, 12.3. HRMS (ESI): m/z [M+H]⁺ calcd forC₂₁H₂₃N₂O 319.1810, found 319.1807. HPLC: t_(R)=5.88 min, 96.0%.

5-Methyl-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxylic acid (19a)

To a mixture of 4-methylaniline (2.14 g, 20 mmol) in concentrated HCl(8.0 mL) was added a solution of NaNO₂ (1.4 g, 21 mmol) in H₂O (6.0 mL)dropwise at 0° C. The mixture was stirred at 0° C. for 1 h followed bythe addition of a solution of NaN₃ (1.3 g, 20 mmol) in H₂O (6.0 mL) at0° C. The resulting mixture was stirred for another 1 h, extracted withdiethyl ether for three times. The combined organic layers were washedwith brine, dried over Na₂SO₄, and concentrated to give the residue. Tothe residue was added ethyl acetoacetate (2.86 g, 22 mmol) and asolution of NaOEt (2.04 g, 30 mmol) in EtOH (120 mL) at roomtemperature. The mixture was stirred at 80° C. overnight. After coolingto room temperature, the solvent was removed under vacuum, and 1M HCl(250 mL) was added to generate the precipitate. The solid was collectedand washed with water to offer the crude product which wasrecrystallized from ethanol to give 19a (2.0 g, 46%). ¹H-NMR (400 MHz,DMSO-d₆) δ 13.08 (s, 1H), 7.42-7.38 (m, 4H), 2.41 (s, 3H), 2.36 (s, 3H);¹³C-NMR (100 MHz, DMSO-d₆) δ 163.1, 140.3, 136.8, 133.3, 130.5, 125.7,123.2, 21.2, 10.1.

5-Methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxylic acid (19b)

Compound 19b was prepared from 2-Methylaniline (2.14 g, 20 mmol) in asimilar manner to that described for compound 19a. Yield: 2.4 g, 55%.¹H-NMR (400 MHz, DMSO-d₆) δ 13.16 (s, 1H), 7.57-7.52 (m, 2H), 7.46-7.44(m, 2H), 2.32 (s, 3H), 2.00 (s, 3H); ¹³C-NMR (100 MHz, DMSO-d₆) δ 163.0,140.1, 136.5, 135.5, 134.6, 131.7, 131.2, 127.8, 127.6, 17.1, 9.6.

1-(2,4-Dimethylphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid(19c)

Compound 19c was prepared from 2,4-Dimethylaniline (2.42 g, 20 mmol) ina similar manner to that described for compound 19a. Yield: 3.4 g, 73%.¹H-NMR (400 MHz, DMSO-d₆) δ 13.01 (s, 1H), 7.28-7.24 (m, 2H), 7.20-7.18(m, 1H), 2.34 (s, 3H), 2.26 (s, 3H), 1.88 (s, 3H); ¹³C-NMR (100 MHz,DMSO-d₆) δ 163.0, 140.9, 140.1, 136.4, 135.1, 132.2, 132.1, 128.0,127.5, 21.1, 17.0, 9.6.

1-(2-Fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (19d)

Compound 19d was prepared from 2-Fluoroaniline (2.22 g, 20 mmol) in asimilar manner to that described for compound 19a. Yield: 2.6 g, 60%.¹H-NMR (400 MHz, DMSO-d₆) δ 13.24 (s, 1H), 7.74-7.68 (m, 2H), 7.64-7.56(m, 1H), 7.52-7.45 (m, 1H), 2.40 (s, 3H); ¹³C-NMR (100 MHz, DMSO-d₆) δ162.8, 157.5, 155.0, 140.8, 136.7, 133.5, 133.5, 129.5, 126.1, 123.2,123.0, 117.6, 117.4, 9.5.

1-(2-Cyanophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (19e)

Compound 19e was prepared from 2-Aminobenzonitrile (2.36 g, 20 mmol) ina similar manner to that described for compound 19a. Yield: 4.56 g, 71%.¹H-NMR (400 MHz, DMSO-d₆) δ 13.37 (s, 1H), 8.23-8.21 (d, J=6.8 Hz, 1H),8.05-8.01 (t, J=7.2 Hz), 7.92-7.87 (m, 2H), 2.47 (s, 3H); ¹³C-NMR (100MHz, DMSO-d₆) δ 162.7, 140.6, 136.9, 136.8, 135.3, 134.9, 132.0, 128.8,115.6, 110.5, 9.8.

1-(2-Methoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (19f)

Compound 19f was prepared from o-Anisidine (2.46 g, 20 mmol) in asimilar manner to that described for compound 19a. Yield: 3.7 g, 80%.¹H-NMR (400 MHz, DMSO-d₆) δ 13.14 (s, 1H), 7.66-7.62 (t, J=8.0 Hz, 1H),7.49-7.47 (d, J=8.0 Hz, 1H), 7.35-7.33 (d, J=8.0 Hz, 1H), 7.20-7.16 (t,J=8.0 Hz, 1H), 3.80 (s, 3H), 2.31 (s, 3H); ¹³C-NMR (100 MHz, DMSO-d₆) δ163.0, 154.1, 140.8, 136.3, 132.7, 128.9, 123.9, 121.3, 113.3, 56.4,9.5.

1-(2-Bromophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (19g)

Compound 19g was prepared from 2-Bromoaniline (3.4 g, 20 mmol) in asimilar manner to that described for compound 19a. Yield: 4.5 g, 80%.¹H-NMR (400 MHz, DMSO-d₆) δ 13.26 (s, 1H), 7.98-7.96 (m, 1H), 7.73-7.62(m, 3H), 2.34 (s, 3H); ¹³C-NMR (100 MHz, DMSO-d₆) δ 167.6, 145.3, 141.3,139.3, 138.8, 138.1, 134.9, 134.4, 125.9, 14.4.

5-Methyl-1-(2-morpholinophenyl)-1H-1,2,3-triazole-4-carboxylic acid(19h)

Compound 19h was prepared from 2-Morpholinoanilinein (3.56 g, 20 mmol)in a similar manner to that described for compound 19a. Yield: 4.78 g,83%. ¹H-NMR (400 MHz, DMSO-d₆) δ 13.17 (s, 1H), 7.63-7.59 (t, J=8.0 Hz,1H), 7.44-7.42 (d, J=8.0 Hz, 1H), 7.33-7.31 (d, J=8.0 Hz, 1H), 7.30-7.26(t, J=8.0 Hz, 1H), 3.42 (br s, 4H), 2.63 (br s, 4H), 2.38 (s, 3H);¹³C-NMR (100 MHz, DMSO-d₆) δ 162.9, 148.0, 140.5, 136.7, 132.3, 129.2,129.1, 124.0, 120.9, 66.6, 51.4, 10.0.

1-([1,1′-biphenyl]-2-yl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid(19i)

Compound 19i was prepared from 2-Phenylaniline (3.38 g, 20 mmol) in asimilar manner to that described for compound 19a. Yield: 3.6 g, 65%.¹H-NMR (400 MHz, DMSO-d₆) δ 7.72-7.68 (m, 1H), 7.63-7.61 (m, 2H),7.53-7.51 (m, 1H), 7.26-7.21 (m, 3H), 7.02-6.96 (m, 2H), 1.97 (s, 3H);¹³C-NMR (100 MHz, DMSO-d₆) δ 164.2, 140.1, 138.9, 137.9, 137.5, 133.5,131.5, 131.4, 129.3, 129.0, 128.8, 128.4, 128.3, 9.5.

1-(2-Acetylphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (19j)

Compound 19j was prepared from 2-Acetylaniline (2.7 g, 20 mmol) in asimilar manner to that described for compound 19a. Yield: 1.9 g, 40%.¹H-NMR (400 MHz, DMSO-d₆) δ 8.02-7.99 (m, 1H), 7.77-7.73 (m, 2H),7.61-7.59 (m, 1H), 2.32 (s, 3H), 2.26 (s, 3H); ¹³C-NMR (100 MHz,DMSO-d₆) δ 199.0, 163.0, 140.7, 136.5, 136.3, 133.3, 132.6, 131.5,130.4, 128.8, 29.3, 9.8.

1-(2-Carbamoylphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (19k)

Compound 19k was prepared from 2-Aminobenzamide (2.72 g, 20 mmol) in asimilar manner to that described for compound 19a. Yield: 3.2 g, 65%.¹H-NMR (400 MHz, DMSO-d₆) δ 13.10 (s, 1H), 7.93 (s, 1H), 7.70-7.68 (m,1H), 7.67-7.62 (m, 2H), 7.55-7.52 (m, 1H), 7.38 (s, 1H), 2.38 (s, 3H);¹³C-NMR (100 MHz, DMSO-d₆) δ 167.6, 163.2, 140.8, 136.0, 135.9, 131.4,131.0, 129.1, 128.5, 129.1, 128.5, 128.3, 9.9.

1-(4-Fluoro-2-nitrophenyl)-5-methyl

1H-1,2,3-triazole-4-carboxylic acid (19l). Compound 19l was preparedfrom 4-Fluoro-2-nitroaniline (3.12 g, 20 mmol) in a similar manner tothat described for compound 19a. Yield: 1.6 g, 30%. ¹H-NMR (400 MHz,DMSO-d₆) δ 13.29 (s, 1H), 7.86-7.83 (m, 2H), 7.55-7.54 (d, J=7.2 Hz,1H), 2.43 (s, 3H); ¹³C-NMR (100 MHz, DMSO-d₆) δ 167.5, 165.5, 151.3,146.0, 141.3, 135.9, 125.4, 125.0, 116.6, 14.4.

1-(2,3-Dimethylphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid(19m)

Compound 19m was prepared from 2,3-Dimethylaniline (2.42 g, 20 mmol) ina similar manner to that described for compound 19a. Yield: 3.23 g, 70%.¹H-NMR (400 MHz, DMSO-d₆) δ 13.14 (s, 1H), 7.46-7.45 (m, 1H), 7.36-7.32(m, 1H), 7.26-7.25 (m, 1H), 2.36 (s, 3H), 2.30 (s, 3H), 1.81 (s, 3H);¹³C-NMR (100 MHz, DMSO-d₆) δ 167.8, 144.9, 143.9, 141.2, 139.3, 138.9,137.0, 131.6, 130.1, 24.9, 18.7, 14.3.

5-Methyl-1-(naphthalen-1-yl)-1H-1,2,3-triazole-4-carboxylic acid (19n)

Compound 19n was prepared from 1-Aminonaphthalene (2.86 g, 20 mmol) in asimilar manner to that described for compound 19a. Yield: 3.64 g, 72%.¹H-NMR (400 MHz, DMSO-d₆) δ 13.15 (s, 1H), 8.27-8.25 (d, J=8.0 Hz, 1H),8.16-8.14 (d, J=8.0 Hz, 1H), 7.80-7.30 (m, 2H), 7.69-7.65 (t, J=8.0 Hz,1H), 7.62-7.58 (t, J=8.0 Hz, 1H), 7.14-7.12 (d, J=8.0 Hz, 1H), 2.31 (s,3H); ¹³C-NMR (100 MHz, DMSO-d₆) δ 163.0, 141.1, 136.7, 134.1, 131.5,129.2, 128.9, 128.8, 127.9, 127.7, 126.2, 126.0, 122.0, 9.7.

1-(3-Chlorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (19o)

Compound 19o was prepared from 3-Chloroaniline (2.54 g, 20 mmol) in asimilar manner to that described for compound 19a. Yield: 3.2 g, 68%.¹H-NMR (400 MHz, DMSO-d₆) δ 13.15 (s, 1H), 7.78 (s, 1H), 7.67-7.63 (m,2H), 7.61-7.59 (m, 1H), 2.48 (s, 3H); ¹³C-NMR (100 MHz, DMSO-d₆) δ162.9, 139.7, 136.9, 136.8, 134.3, 131.8, 130.5, 125.9, 124.8, 10.1.

5-Ethyl-1-(2-fluorophenyl)-1H-1,2,3-triazole-4-carboxylic acid (19p)

Compound 19p was prepared from 2-Flouroaniline (2.22 g, 20 mmol) andethyl 3-oxopentanoatein (3.16 g, 22 mmol) in a similar manner to thatdescribed for compound 19a. Yield: 3.76 g, 80%. ¹H-NMR (400 MHz,DMSO-d₆) δ 13.31 (s, 1H), 7.77-7.74 (m, 2H), 7.64-7.59 (t, J=8.8 Hz,1H), 7.52-7.48 (t, J=8.0 Hz, 1H), 2.84-2.78 (q, J=7.2 Hz, 2H), 1.02-0.98(t, J=7.2 Hz, 3H); ¹³C-NMR (100 MHz, DMSO-d₆) δ 167.4, 162.6, 160.1,150.5, 140.9, 138.6, 138.5, 134.6, 130.9, 130.8, 122.3, 122.1, 21.6,17.6.

1-(2-Fluorophenyl)-5-isopropyl-1H-1,2,3-triazole-4-carboxylic acid (19q)

Compound 19q was prepared from 2-Flouroaniline (2.22 g, 20 mmol) andethyl 4-methyl-3-oxopentanoate (3.5 g, 22 mmol) in a similar manner tothat described for compound 19a. Yield: 1.2 g, 25%. ¹H-NMR (400 MHz,DMSO-d₆) δ 13.01 (s, 1H), 7.77-7.74 (m, 2H), 7.64-7.60 (t, J=8.0 Hz,1H), 7.52-7.48 (t, J=8.0 Hz, 1H), 3.24-3.20 (m, 1H), 1.23-1.21 (d, J=6.8Hz, 6H); ¹³C-NMR (100 MHz, DMSO-d₆) δ 167.6, 162.8, 160.3, 153.5, 140.6,138.7, 138.6, 135.0. 130.8, 122.2, 122.0, 29.5, 24.6.

General procedure for the synthesis of compounds 20-46.

5-Methyl-N-(pyridin-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide(20)

To a solution of 2-aminopyridine (94 mg, 1.0 mmol) and 19a (260 mg, 1.2mmol) in DCE (5 mL) was added PyCIU (398 mg, 1.2 mmol) and DIPEA (516mg, 4.0 mmol). The mixture was stirred at 80° C. overnight. Aftercooling to room temperature, the solvent was removed under vacuum. Tothe residue was added ethyl acetate (30 mL), and the resulting mixturewas washed with brine, dried over Na₂SO₄ and concentrated. The crudematerial was purified by column chromatography (Hexane/AcOEt, v/v=2/1)to give the title product as a white solid (117 mg, 40%). ¹H-NMR (400MHz, DMSO-d₆) δ 9.89 (s, 1H), 8.41-8.40 (d, J=4.0 Hz, 1H), 8.21-8.19 (d,J=8.0 Hz, 1H), 7.91-7.87 (t, J=8.0 Hz, 1H), 7.57-7.55 (d, J=8.0 Hz, 2H),7.49-7.47 (d, J=8.0 Hz, 2H), 7.23-7.20 (t, J=8.0 Hz, 1H), 2.59 (s, 3H),2.45 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ 159.7, 151.1, 147.9, 140.4,138.3, 137.7, 132.9, 130.2, 125.1, 119.7, 114.0, 21.3, 9.8. HRMS (ESI):m/z [M+H]⁺ calcd for C₁₆H₁₆N₅O, 294.1355; found, 294.1353. HPLC:t_(R)=4.02 min, 99.2%.

5-Methyl-N-(6-methylpyridin-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide(21)

Compound 21 was synthesized from 6-Methyl-2-aminopyridine (108 mg, 1.0mmol) and 19a in a similar manner to that described for compound 20.White solid. Yield: 154 mg, 50%. ¹H-NMR (400 MHz, CDCl₃) δ 9.62 (s, 1H),8.14-8.12 (d, J=8.0 Hz, 1H), 7.64-7.60 (t, J=8.0 Hz, 1H), 7.39-7.34 (m,4H), 6.94-6.92 (d, J=8.0 Hz, 1H), 2.65 (s, 3H), 2.50 (s, 3H), 2.46 (s,3H); ¹³C-NMR (100 MHz, CDCl₃) δ 159.7, 157.2, 150.4, 140.3, 138.4,138.2, 137.6, 132.9, 130.2, 125.1, 119.2, 110.7, 24.1, 21.2, 9.8. HRMS(ESI): m/z [M+H]⁺ calcd for C₁₇H₁₈N₅O, 308.1511; found, 308.1515. HPLC:t_(R)=⁷0.15 min, 99.4%.

N-(4,5-diphenylthiazol-2-yl)-5-methyl-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide(22)

Compound 22 was synthesized from 2-Amino-4,5-diphenylthiazole (252 mg,1.0 mmol) and 19a in a similar manner to that described for compound 20.White solid. Yield: 252 mg, 56%. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.61 (s,1H), 7.58-7.56 (d, J=8.0 Hz, 2H), 7.50 (m, 4H), 7.41-7.33 (m, 8H), 2.60(s, 3H), 2.45 (s, 3H); ¹³C-NMR (100 MHz, DMSO-d₆) δ 160.0, 155.6, 144.6,140.5, 139.3, 137.1, 135.1, 133.1, 132.2, 130.6, 129.7, 129.4, 129.0,128.7, 128.5, 128.2, 126.4, 125.7, 21.2, 10.0. HRMS (ESI): m/z [M+H]⁺calcd for C₂₆H₂₂N₅OS, 452.1545; found, 452.1550. HPLC: t_(R)=5.00 min,99.0%.

5-Methyl-N-(1-methyl-1H-benzo[d]imidazol-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide(23)

Compound 23 was synthesized from 2-Amino-1-methylbenzimidazole (147 mg,1.0 mmol) and 19a in a similar manner to that described for compound 20.White solid. Yield: 253 mg, 73%. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.70 (s,1H), 7.56-7.45 (m, 6H), 7.28-7.24 (m, 2H), 3.70 (s, 3H), 2.69 (s, 3H),2.45 (s, 3H). HRMS (ESI): m/z [M+H]⁺ calcd for C₁₉H₁₉N₆O, 347.1620;found, 347.1617. HPLC: t_(R)=2.32 min, 98.0%.

5-Methyl-N-(3-methylisoxazol-5-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide(24)

Compound 24 was synthesized from 5-Amino-3-methylisoxazole (98 mg, 1.0mmol) and 19a in a similar manner to that described for compound 20.White solid. Yield: 47 mg, 16%. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.78 (s,1H), 7.40-7.38 (d, J=8.0 Hz, 2H), 7.35-7.33 (d, J=8.0 Hz, 2H), 6.33 (s,1H), 2.64 (s, 3H), 2.47 (s, 3H), 2.31 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃)δ 161.6, 159.6, 157.0, 140.7, 138.4, 137.0, 132.6, 130.3, 125.0, 89.4,21.3, 11.9, 9.7. HRMS (ESI): m/z [M+H]⁺ calcd for C₁₅H₁₆N₅O₂, 298.1304;found, 298.1300. HPLC: t_(R)=7.38 min, 97.6%.

5-Methyl-N-(pyridin-2-ylmethyl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide(25)

Compound 25 was synthesized from 2-Picolylamine (108 mg, 1.0 mmol) and19a in a similar manner to that described for compound 20. Yield: 166mg, 54%. ¹H-NMR (400 MHz, CDCl₃) δ 8.55-8.54 (d, J=4.8 Hz 1H), 8.20 (s,1H), 7.63-7.61 (t, J=8 Hz, 1H), 7.41-7.39 (m, 5H), 7.17-7.14 (t, J=4.8Hz 1H), 4.82 (s, 2H), 2.60 (s, 3H), 2.41 (s, 3H); ¹³C-NMR (100 MHz,CDCl₃) δ 161.5, 161.4, 156.9, 149.2, 140.1, 138.3, 136.7, 133.1, 130.1,125.0, 122.3, 121.7, 44.2, 21.2, 9.6. HRMS (ESI): m/z [M+H]⁺ calcd forC₁₇H₁₈N₅O, 308.1511; found, 308.1513. HPLC: t_(R)=2.04 min, 99.9%.

5-Methyl-N-(2-methyl-4-oxo-4H-chromen-7-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide(26)

Compound 26 was synthesized from 7-Amino-2-methyl-4H-chromen-4-one (175mg, 1.0 mmol) and 19a in a similar manner to that described for compound20. Yellow solid. Yield: 86 mg, 23%. ¹H-NMR (400 MHz, CDCl₃) δ 9.32 (s,1H), 8.21 (s, 1H), 8.18-8.16 (d, J=8.4 Hz 1H), 7.44-7.35 (m, 5H), 6.17(s, 1H), 2.68 (s, 3H), 2.48 (s, 3H), 2.39 (s, 3H); ¹³C-NMR (100 MHz,CDCl₃) δ 177.6, 166.2, 161.0, 159.5, 157.4, 142.2, 140.6, 138.0, 132.8,130.3, 126.6, 125.0, 119.6, 116.6, 110.4, 107.2, 21.3, 20.6, 9.8. HRMS(ESI): m/z [M+H]⁺ calcd for C₂₁H₁₉N₄O₃ 375.1457, found 375.1458. HPLC:t_(R)=6.00 min, 98.4%.

5-Methyl-N-(quinolin-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide(27)

Compound 27 was synthesized from 2-Aminoquinoline (44 mg, 0.3 mmol) and19a (78 mg, 0.36 mmol) in a similar manner to that described forcompound 20. White solid. Yield: 50 mg, 49%. ¹H-NMR (400 MHz, DMSO-d₆) δ10.19 (s, 1H), 8.49-8.47 (d, J=8.8 Hz, 1H), 8.42-8.40 (d, J=8.8 Hz, 1H),8.00-7.98 (d, J=8.0 Hz, 1H), 7.91-7.89 (d, J=8.0 Hz, 1H), 7.79-7.75 (t,J=8.0 Hz, 1H), 7.59-7.57 (d, J=8.0 Hz, 2H), 7.50-7.48 (d, J=8.0 Hz, 2H),2.60 (s, 3H), 2.40 (s, 3H); ¹³C-NMR (100 MHz, DMSO-d₆) δ 160.0, 150.8,146.8, 140.5, 139.2, 138.6, 137.9, 133.1, 130.6, 130.6, 128.3, 127.7,126.4, 125.7, 125.7, 114.6, 21.2, 9.9. HRMS (ESI): m/z [M+H]⁺ calcd forC₂₀H₁₈N₅O, 344.1511; found, 344.1511. HPLC: t_(R)=8.82 min, 99.6%.

5-Methyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide(28)

Compound 28 was synthesized from 2-Aminoquinoline (44 mg, 0.3 mmol) and19b (78 mg, 0.36 mmol) in a similar manner to that described forcompound 20. Colorless solid. Yield: 62 mg, 60%. ¹H-NMR (400 MHz,DMSO-d₆) δ 10.22 (s, 1H), 8.49-8.47 (d, J=8.8 Hz, 1H), 8.42-8.40 (d,J=8.8 Hz, 1H), 8.00-7.98 (d, J=8.0 Hz, 1H), 7.91-7.89 (d, J=8.0 Hz, 1H),7.69 (t, J=8.0 Hz, 1H), 7.61-7.56 (m, 3H), 7.51-7.50 (m, 2H), 2.45 (s,3H), 2.04 (s, 3H); ¹³C-NMR (100 MHz, DMSO-d₆) δ 160.0, 150.8, 146.8,139.5, 139.1, 137.6, 135.5, 134.4, 131.8, 131.4, 130.7, 128.3, 127.8,127.7, 127.7, 126.4, 125.8, 114.7, 17.2, 9.4. HRMS (ESI): m/z [M+H]⁺calcd for C₂₀H₁₈N₅O, 344.1511, found, 344.1510. HPLC: t_(R)=8.75 min,98.2%.

N-(benzo[d]thiazol-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide(29)

Compound 29 was synthesized from 2-Aminobenzothiazole (45 mg, 0.3 mmol)and 19b (78 mg, 0.36 mmol) in a similar manner to that described forcompound 20. White solid. Yield: 70 mg, 67%. ¹H-NMR (400 MHz, DMSO-d₆) δ12.83 (s, 1H), 8.18 (s, 1H), 7.96 (s, 1H), 7.73-7.63 (m, 5H), 7.51 (s,1H), 2.58 (s, 3H), 2.18 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ 159.0,156.8, 148.6, 139.6, 136.4, 135.4, 134.0, 132.2, 131.6, 131.0, 127.2,127.1, 126.3, 124.0, 121.3, 121.2, 17.2, 9.2. HRMS (ESI): m/z [M+H]⁺calcd for C₁₈H₁₆N₅OS, 350.1076; found, 350.1063. HPLC: t_(R)=9.09 min,99.4%.

5-Methyl-N-(4-phenylthiazol-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide(30)

Compound 30 was synthesized from 2-Amino-4-phenylthiazole (53 mg, 0.3mmol) and 19b (78 mg, 0.36 mmol) in a similar manner to that describedfor compound 20. White solid. Yield: 73 mg, 70%. ¹H-NMR (400 MHz,DMSO-d₆) δ 12.51 (s, 1H), 7.99-7.97 (m, 2H), 7.73 (s, 1H), 7.62-7.55 (m,2H), 7.50-7.44 (m, 4H), 7.37-7.35 (m, 1H), 2.43 (s, 3H), 2.03 (s, 3H);¹³C-NMR (100 MHz, DMSO-d₆) δ 164.7, 162.4, 154.3, 144.7, 141.6, 140.3,139.4, 139.2, 136.6, 136.1, 133.9, 133.0, 132.6, 132.4, 131.0, 113.8,21.9, 14.2. HRMS (ESI): m/z [M+H]⁺ calcd for C₂₀H₁₈N₅OS, 370.1232;found, 350.1063. HPLC: t_(R)=12.08 min, 99.0%.

5-Methyl-N-(naphthalen-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide(31)

Compound 31 was synthesized from 2-Aminonaphthalene (43 mg, 0.3 mmol)and 19b (78 mg, 0.36 mmol) in a similar manner to that described forcompound 20. White solid. Yield: 58 mg, 57%. ¹H-NMR (400 MHz, CDCl₃) δ9.28 (s, 1H), 8.47 (s, 1H), 7.87-7.81 (m, 3H), 7.67-7.64 (dd, J₁=1.6 Hz,J₂=8.8 Hz, 1H), 7.53-7.39 (m, 5H), 7.26 (s, 1H), 2.53 (s, 3H), 2.09 (s,3H); ¹³C-NMR (100 MHz, CDCl₃) δ 159.4, 138.4, 138.1, 135.5, 135.2,134.3, 133.9, 131.5, 130.8, 130.7, 128.8, 127.7, 127.6, 127.2, 127.1,126.5, 125.0, 119.8, 116.4, 17.2, 9.2. HRMS (ESI): m/z [M+H]⁺ calcd forC₂₁H₁₉N₄O, 343.1559; found, 343.1561. HPLC: t_(R)=11.64 min, 98.6%.

1-(2,4-Dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide(32)

Compound 32 was synthesized from 2-Aminoquinoline (44 mg, 0.3 mmol) and19c (83 mg, 0.36 mmol) in a similar manner to that described forcompound 20. White solid. Yield: 74 mg, 69%. ¹H-NMR (400 MHz, CDCl₃) δ9.94 (s, 1H), 8.57-8.55 (d, J=8.8 Hz, 1H), 8.23-8.21 (d, J=8.8 Hz, 1H),7.93-7.91 (d, J=8.0 Hz, 1H), 7.82-7.80 (d, J=8.0 Hz, 1H), 7.71-7.67 (t,J=8.0 Hz, 1H), 7.49-7.45 (t, J=8.0 Hz, 1H), 7.26-7.24 (d, J=8.0 Hz, 1H),7.20-7.18 (d, J=8.0 Hz, 1H), 7.15-7.13 (d, J=8.0 Hz, 1H), 2.51 (s, 3H),2.44 (s, 3H), 2.03 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ 160.1, 150.6,141.1, 138.9, 138.4, 137.7, 135.1, 132.1, 131.7, 129.9, 127.8, 127.7,127.5, 126.9, 126.4, 125.1, 114.2, 21.5, 17.1, 9.3. HRMS (ESI): m/z[M+H]⁺ calcd for C₂₁H₂₀N₅O 358.1668, found 358.1661. HPLC: t_(R)=17.12min, 99.9%.

1-(2-Fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide(20)

Compound 33 was synthesized from 2-Aminoquinoline (44 mg, 0.3 mmol) and19d (80 mg, 0.36 mmol) in a similar manner to that described forcompound 20. White solid. Yield: 52 mg, 50%. ¹H-NMR (400 MHz, DMSO-d₆) δ10.25 (s, 1H), 8.46-8.44 (m, 2H), 7.97-7.54 (m, 9H), 2.52 (s, 3H);¹³C-NMR (100 MHz, DMSO-d₆) δ 159.8, 157.5, 155.0, 150.8, 146.8, 140.2,139.1, 137.7, 133.7, 130.6, 129.5, 128.2, 127.7, 126.4, 126.2, 125.8,123.0, 117.7, 117.5, 114.7, 9.3. HRMS (ESI): m/z [M+H]⁺ calcd forC₁₉H₁₅FN₅O, 348.1261; found, 348.1252. HPLC: t_(R)=9.53 min, 99.9%.

1-(2-Cyanophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide(34)

Compound 34 was synthesized from 2-Aminoquinoline (44 mg, 0.3 mmol) and19e (82 mg, 0.36 mmol) in a similar manner to that described forcompound 20. White solid. Yield: 60 mg, 57%. ¹H-NMR (400 MHz, DMSO-d₆) δ10.35 (s, 1H), 8.49-8.46 (d, J=8.8 Hz, 1H), 8.40-8.38 (d, J=8.8 Hz, 1H),8.27-8.25 (d, J=8.0 Hz, 1H), 8.08-8.04 (t, J=8.0 Hz, 1H), 7.99-7.96 (t,2H), 7.94-7.90 (t, J=8.0 Hz, 2H), 7.79-7.75 (t, J=8.0 Hz, 1H), 7.57-7.53(t, J=8.0 Hz, 1H), 2.60 (s, 3H); ¹³C-NMR (100 MHz, DMSO-d₆) δ 159.7,150.8, 146.8, 140.1, 139.1, 138.0, 136.6, 135.4, 135.1, 132.1, 130.7,128.8, 128.3, 127.8, 126.4, 125.8, 115.6, 114.9, 110.5, 9.6. HRMS (ESI):m/z [M+H]⁺ calcd for C₂₀H₁₅N₆O, 355.1307; found 355.1304. HPLC:t_(R)=7.45 min, 99.8%.

1-(2-Methoxyphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide(35)

Compound 35 was synthesized from 2-Aminoquinoline (44 mg, 0.3 mmol) and19f (84 mg, 0.36 mmol) in a similar manner to that described forcompound 20. White solid. Yield: 52 mg, 48%. ¹H-NMR (400 MHz, DMSO-d₆) δ10.28 (s, 1H), 8.61-8.51 (m, 2H), 8.09 (m, 1H), 8.01 (m, 1H), 7.88 (m,1H), 7.78 (m, 1H), 7.66 (m, 2H), 7.52-7.47 (m, 1H), 7.35-7.32 (m, 1H),3.97-3.94 (q, J=4 Hz, 3H), 2.56-2.53 (q, J=4 Hz, 3H); ¹³C-NMR (100 MHz,DMSO-d₆) δ 160.0, 154.1, 150.9, 146.2, 140.2, 139.1, 137.3, 132.9,130.6, 128.9, 128.2, 127.7, 126.4, 125.7, 123.7, 121.4, 114.7, 113.4,56.5, 9.4. HRMS (ESI): m/z [M+H]⁺ calcd for C₂₀H₁₈N₅O₂, 360.1460; found,360.1460. HPLC: t_(R)=8.88 min, 99.8%.

1-(2-Bromophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide(21)

Compound 36 was synthesized from 2-Aminoquinoline (44 mg, 0.3 mmol) and19g (100 mg, 0.36 mmol) in a similar manner to that described forcompound 20. White solid. Yield: 83 mg, 68%. ¹H-NMR (400 MHz, DMSO-d₆) δ10.26 (s, 1H), 8.48-8.46 (d, J=8.0 Hz, 1H), 8.41-8.39 (d, J=8.0 Hz, 1H),8.02-8.99 (t, J=8.8 Hz, 2H), 7.91-7.89 (d, J=8.0 Hz, 1H), 7.77-7.67 (m,4H), 7.57-7.53 (d, J=8.0 Hz, 1H), 2.46 (s, 3H); ¹³C-NMR (100 MHz,DMSO-d₆) δ 164.6, 155.5, 151.6, 144.7, 143.9, 142.3, 139.2, 138.9,138.3, 135.4, 135.0, 134.5, 133.0, 132.5, 131.2, 130.6, 125.9, 119.6,14.2. HRMS (ESI): m/z [M+H]⁺ calcd for C₁₉H₁₅BrN₅O₂, 408.0460; found,408.0458. HPLC: t_(R)=8.21 min, 99.9%.

5-Methyl-1-(2-morpholinophenyl)-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide(28)

Compound 37 was synthesized from 2-Aminoquinoline (44 mg, 0.3 mmol) and19h (104 mg, 0.36 mmol) in a similar manner to that described forcompound 20. White solid. Yield: 60 mg, 48%. ¹H-NMR (400 MHz, DMSO-d₆) δ10.20 (s, 1H), 8.48-8.46 (d, J=8.8 Hz, 1H), 8.43-8.40 (d, J=8.8 Hz, 1H),7.99-7.97 (d, J=8.4 Hz, 1H), 7.90-7.88 (d, J=8.4 Hz, 1H), 7.78-7.74 (t,J=8.0 Hz, 1H), 7.66-7.62 (t, J=8.0 Hz, 1H), 7.57-7.53 (t, J=8.0 Hz, 1H),7.50-7.48 (d, J=8.0 Hz, 1H), 7.37-7.33 (t, J=8.0 Hz, 1H), 7.31-7.29 (d,J=8.0 Hz, 1H), 3.45 (br s, 4H), 2.67 (br s, 4H), 2.50 (s, 3H); ¹³C-NMR(100 MHz, DMSO-d₆) δ 159.9, 150.8, 146.8, 139.8, 139.1, 137.8, 132.4,130.6, 129.3, 129.0, 128.3, 127.7, 126.4, 125.7, 124.1, 121.0, 114.7,66.6, 51.4, 9.7. HRMS (ESI): m/z [M+H]⁺ calcd for C₂₃H₂₃N₆O₂, 415.1882;found, 415.1873. HPLC: t_(R)=10.48 min, 99.6%.

1-([1,1′-biphenyl]-2-yl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide(38)

Compound 38 was synthesized from 2-Aminoquinoline (44 mg, 0.3 mmol) and19i (100 mg, 0.36 mmol) in a similar manner to that described forcompound 20. White solid. Yield: 70 mg, 58%. ¹H-NMR (400 MHz, DMSO-d₆) δ10.11 (s, 1H), 8.45-8.43 (d, J=8.0 Hz, 1H), 8.33-8.31 (d, J=8.0 Hz, 1H),7.98-7.96 (d, J=8.0 Hz, 1H), 7.89-7.87 (d, J=8.0 Hz, 1H), 7.81-7.69 (m,5H), 7.56-7.52 (t, J=7.2 Hz, 1H), 7.34-7.32 (m, 3H), 7.09-7.07 (m, 2H),2.16 (s, 3H); ¹³C-NMR (100 MHz, DMSO-d₆) δ 159.7, 150.7, 146.8, 139.6,139.1, 137.4, 137.2, 132.8, 131.9, 131.5, 130.6, 129.5, 129.2, 128.7,128.5, 128.2, 127.7, 126.4, 125.8, 114.7, 9.28. HRMS (ESI): m/z [M+H]⁺calcd for C₂₅H₂₀N₅O, 406.1668; found, 406.1665. HPLC: t_(R)=11.17 min,99.9%.

1-(2-Acetylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide(39)

Compound 39 was synthesized from 2-Aminoquinoline (44 mg, 0.3 mmol) and19j (88 mg, 0.36 mmol) in a similar manner to that described forcompound 20. Brown solid. Yield: 53 mg, 48%. ¹H-NMR (400 MHz, DMSO-d₆) δ10.37 (s, 1H), 8.65-8.63 (d, J, =8.8 Hz, 1H), 8.58-8.56 (d, J=8.8 Hz,1H), 8.30-8.28 (d, J=7.2 Hz, 1H), 8.16-8.14 (d, J=8.0 Hz, 1H), 8.07-8.01(m, 3H), 7.95-7.89 (m, 2H), 7.74-7.70 (t, J=7.2 Hz, 1H), 2.67 (s, 6H);¹³C-NMR (100 MHz, DMSO-d₆) δ 203.7, 164.7, 155.6, 151.6, 144.9, 143.9,142.3, 140.9, 138.2, 137.1, 136.4, 135.4, 133.6, 133.0, 132.5, 131.2,130.5, 119.5, 34.1, 14.3. HRMS (ESI): m/z [M+H]⁺ calcd for C₂₁H₁₈N₅O₂,372.1460; found, 372.1455. HPLC: t_(R)=7.39 min, 99.2%.

1-(2-Carbamoylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide(40)

Compound 40 was synthesized from 2-Aminoquinoline (44 mg, 0.3 mmol) and19k (88 mg, 0.36 mmol) in a similar manner to that described forcompound 20. Buff solid. Yield: 55 mg, 49%. ¹H-NMR (400 MHz, DMSO-d₆) δ10.13 (s, 1H), 8.48-8.46 (d, J=8.8 Hz, 1H), 8.42-8.39 (d, J=8.8 Hz, 1H),8.06 (s, 1H), 7.99-7.97 (d, J=8.0 Hz, 1H), 7.90-7.88 (d, J=8.0 Hz, 1H),7.80-7.74 (m, 4H), 7.68-7.66 (m, 1H), 7.57-7.53 (t, J=8.0 Hz, 1H), 7.49(s, 1H), 2.50 (s, 3H); ¹³C-NMR (100 MHz, DMSO-d₆) δ 172.3, 164.8, 155.6,151.6, 145.1, 143.9, 141.7, 139.7, 137.6, 136.2, 135.9, 135.4, 133.9,133.3, 133.0, 132.5, 131.2, 130.5, 119.4, 14.4. HRMS (ESI): m/z [M+H]⁺calcd for C₂₀H₁₇N₆O₂, 373.1413; found, 373.1413. HPLC: t_(R)=2.72 min,95.0%.

1-(4-Fluoro-2-nitrophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide(41)

Compound 41 was synthesized from 2-Aminoquinoline (44 mg, 0.3 mmol) and19l (96 mg, 0.36 mmol) in a similar manner to that described forcompound 20. Yellow solid. Yield: 35 mg, 30%. ¹H-NMR (400 MHz, DMSO-d₆)δ 10.26 (s, 1H), 8.49-8.47 (d, J=8.8 Hz, 1H), 8.40-8.38 (d, J=8.8 Hz,1H), 8.00-7.98 (d, J=8.0 Hz, 1H), 7.92-7.87 (m, 3H), 7.78-7.75 (t, J=8.0Hz, 1H), 7.59-7.54 (m, 2H), 2.55 (s, 3H); ¹³C-NMR (100 MHz, DMSO-d₆) δ160.9, 159.8, 150.8, 146.8, 146.5, 140.8, 139.1, 137.6, 131.3, 130.6,128.6, 127.8, 126.4, 125.8, 120.8, 120.0, 114.9, 111.9, 9.4. HRMS (ESI):m/z [M+H]⁺ calcd for C₁₉H₁₄FN₆O₃, 393.1111; found, 393.1120. HPLC:t_(R)=8.26 min, 95.0%.

1-(2,3-Dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide(42)

Compound 42 was synthesized from 2-Aminoquinoline (44 mg, 0.3 mmol) and19m (85 mg, 0.36 mmol) in a similar manner to that described forcompound 20. White solid. Yield: 72 mg, 67%. ¹H-NMR (400 MHz, CDCl₃) δ9.95 (s, 1H), 8.57-8.55 (d, J=8.4 Hz, 1H), 8.23-8.21 (d, J=8.4 Hz, 1H),7.93-7.91 (d, J=8.8 Hz, 1H), 7.81-7.79 (d, J=8.4 Hz, 1H), 7.71-7.67 (t,J=8.0 Hz, 1H), 7.49-7.45 (t, J=7.2 Hz, 1H), 7.40-7.38 (d, J=7.2 Hz, 1H),7.31-7.27 (t, J=8.0 Hz, 1H), 7.12-7.10 (d, J=8.0 Hz, 1H), 2.50 (s, 3H),2.39 (s, 3H), 1.91 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ 160.1, 150.6,146.9, 139.1, 139.0, 138.4, 137.7, 134.3, 134.0, 132.2, 129.9, 127.8,127.5, 126.5, 126.4, 125.1, 124.8, 114.2, 20.3, 14.0, 9.3. HRMS (ESI):m/z [M+H]⁺ calcd for C₂₁H₂₀N₅O, 358.1668; found, 358.1670. HPLC:t_(R)=11.23 min, 99.9%.

5-Methyl-1-(naphthalen-1-yl)-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide(43)

Compound 43 was synthesized from 2-Aminoquinoline (44 mg, 0.3 mmol) and19n (91 mg, 0.36 mmol) in a similar manner to that described forcompound 20. White solid. Yield: 54 mg, 47%. ¹H-NMR (400 MHz, DMSO-d₆) δ10.56 (s, 1H), 8.76-8.69 (m, 2H), 8.58-8.56 (d, J=8.0 Hz, 1H), 8.46-8.44(d, J=8.0 Hz, 1H), 8.26-8.24 (d, J=8.0 Hz, 1H), 8.19-8.17 (d, J=8.0 Hz,1H), 8.10 (s, 1H), 8.07-8.10 (m, 2H), 7.97-7.95 (m, 1H), 7.92-7.89 (t,J=6.4 Hz, 1H), 7.82 (t, J=6.4 Hz, 1H), 7.49-7.47 (d, J=8.0 Hz, 1H), 2.67(s, 3H); ¹³C-NMR (100 MHz, DMSO-d₆) δ 160.0, 150.9, 146.8, 140.4, 139.2,137.8, 134.1, 131.7, 131.4, 130.7, 129.2, 128.9, 128.8, 128.3, 127.8,127.7, 126.4, 126.3, 126.0, 125.8, 122.1, 114.7, 9.5. HRMS (ESI): m/z[M+H]⁺ calcd for C₂₃H₁₈N₅O, 380.1511; found, 380.1512. HPLC: t_(R)=9.54min, 97.4%.

1-(3-Chlorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide(44)

Compound 44 was synthesized from 2-Aminoquinoline (44 mg, 0.3 mmol) and19o (85 mg, 0.36 mmol) in a similar manner to that described forcompound 20. White solid. Yield: 66 mg, 60%. ¹H-NMR (400 MHz, DMSO-d₆) δ10.22 (s, 1H), 8.48-8.46 (d, J=8.8 Hz, 1H), 8.42-8.40 (d, J=8.8 Hz, 1H),7.99-7.97 (d, J=8.0 Hz, 1H), 7.91-7.88 (m, 2H), 7.78-7.71 (m, 4H),7.57-7.53 (t, J=8.0 Hz, 1H), 2.65 (s, 3H); ¹³C-NMR (100 MHz, DMSO-d₆) δ164.6, 155.6, 151.6, 143.9, 142.7, 141.5, 139.1, 136.6, 135.5, 135.4,133.0, 132.5, 131.2, 130.6, 130.5, 129.6, 119.4, 14.6. HRMS (ESI): m/z[M+H]⁺ calcd for C₁₉H₁₅ClN₅O, 364.0965; found, 364.0952. HPLC:t_(R)=16.54 min, 99.8%.

5-Ethyl-1-(2-fluorophenyl)-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide(45)

Compound 45 was synthesized from 2-Aminoquinoline (44 mg, 0.3 mmol) and19p (85 mg, 0.36 mmol) in a similar manner to that described forcompound 20. White solid. Yield: 65 mg, 60%. ¹H-NMR (400 MHz, DMSO-d₆) δ10.28 (s, 1H), 8.49-8.46 (d, J=8.8 Hz, 1H), 8.42-8.40 (d, J=8.8 Hz, 1H),8.00-7.98 (d, J=8.8 Hz, 1H), 7.91-7.89 (d, J=8.8 Hz, 1H), 7.84-7.75 (m,3H), 7.69-7.65 (t, J=8.0 Hz, 1H), 7.57-7.53 (m, 2H), 2.96-2.91 (q, J 7.2Hz, 2H), 1.11-1.08 (t, J=7.2 Hz, 3H); ¹³C-NMR (100 MHz, DMSO-d₆) δ164.4, 162.6, 160.1, 155.6, 151.6, 149.9, 143.9, 142.1, 138.8, 138.7,135.4, 134.6, 133.0, 132.5, 131.2, 131.0, 130.9, 130.5, 122.4, 122.2,119.5, 21.6, 17.5. HRMS (ESI): m/z [M+H]⁺ calcd for C₂₀H₁₇FN₅O,362.1417; found, 362.1415. HPLC: t_(R)=14.04 min, 99.7%.

1-(2-Fluorophenyl)-5-isopropyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide(46)

Compound 46 was synthesized from 2-Aminoquinoline (44 mg, 0.3 mmol) and19q (90 mg, 0.36 mmol) in a similar manner to that described forcompound 20. White solid. Yield: 78 mg, 69%. ¹H-NMR (400 MHz, DMSO-d₆) δ10.34 (s, 1H), 8.49-8.47 (d, J=8.8 Hz, 1H), 8.43-8.41 (d, J=8.8 Hz, 1H),8.00-7.98 (d, J=8.8 Hz, 1H), 7.91-7.89 (d, J=8.8 Hz, 1H), 7.84-7.75 (m,3H), 7.69-7.65 (t, J=8.0 Hz, 1H), 7.57-7.53 (m, 2H), 3.24-3.20 (m, 1H),1.34-1.32 (d, J=7.2 Hz, 6H); ¹³C-NMR (100 MHz, DMSO-d₆) δ 164.3, 162.8,160.3, 155.6, 153.1, 151.6, 143.9, 142.1, 138.9, 138.8, 135.4, 134.9,133.0, 132.5, 131.2, 131.0, 130.5, 128.4, 128.3, 122.3, 122.1, 119.5,29.7, 24.8. HRMS (ESI): m/z [M+H]⁺ calcd for C₂₁H₁₉FN₅O, 376.1574;found, 376.1581. HPLC: t_(R)=10.69 min, 99.0%.

TABLE 8 HPLC analytic data Compounds Method Retention Time (min) Area(%) 14 (YW1109) A 7.02 99.0 15 (YW1117-2) A 6.42 99.8 16 (YW1114) B12.18 99.5 17 (YW1104) A 5.88 98.0 20 A 4.02 99.6 21 E 7.15 99.7 22 D5.00 99.5 23 C 2.32 99.0 24 A 7.38 98.8 25 C 2.04 100 26 A 6.00 99.2 27A 8.82 99.8 28 A 8.75 99.1 29 A 9.09 99.7 30 A 12.08 99.5 31 A 11.6499.3 32 A 17.12 100 33 A 9.53 100 34 A 7.45 99.9 35 A 8.88 99.9 36 A8.21 100 37 A 10.48 99.8 38 A 11.17 100 39 A 7.39 99.6 40 B 2.72 97.5 41A 8.26 97.5 42 A 11.23 100 43 A 9.54 98.7 44 A 16.54 99.9 45 A 14.0499.9 46 A 10.69 99.5 Method A: 60% acetonitrile/40% H₂O (0.1%trifluoroacetic acid), 1 mL/min, 20 min. Method B: 70% acetonitrile/30%H₂O (0.1% trifluoroacetic acid), 1 mL/min, 20 min. Method C: 80%acetonitrile/20% H₂O (0.1% trifluoroacetic acid), 1 mL/min, 20 min.Method D: 96% acetonitrile/4% H₂O (0.1% trifluoroacetic acid), 1 mL/min,20 min. Method E: 50% acetonitrile/50% H₂O (0.1% trifluoroacetic acid),1 mL/min, 20 min.

Example 2: Synthesis of Pyrazole-Based Wnt/β-Catenin SignalingInhibitors

A variety of pyrazole-based Wnt/β-catenin inhibitors were also preparedaccording to the schemes set forth herein.

(E)-ethyl 2-((dimethylamino)methylene)-3-oxobutanoate (S110)

To a solution of ethyl acetoacetate (2.6 g, 20 mmol) in ethanol (10 mL)was added N,N-Dimethylformamide dimethyl acetal (2.5 g, 21 mmol). Themixture was allowed to stir at 60° C. for 3 h, then cooled to roomtemperature and concentrated to give a crude product (3.6 g, 97%), whichwas used without further purification.

Ethyl 5-methyl-1-(o-tolyl)-1H-pyrazole-4-carboxylate (S111a)

To a solution of the above crude S110 (3.6 g, 19.5 mmol) in ethanol (20mL) was added DIPEA (2.71 g, 21 mmol) and 2-metylphenyhdrazine.HCl (3.3g, 21 mmol). The mixture was allowed to stir at 60° C. for 3 h. Then,the mixture was cooled to room temperature, concentrated to give thecrude product as an oil (4.3 g, 90%).

5-Methyl-1-(o-tolyl)-1H-pyrazole-4-carboxylic acid (S112a)

The above crude product of S111a was dissolved in ethanol. The reactionmixture was allowed to stir at 65° C. for 4 h and concentrated. Theresidue was dissolved in water, acidified to pH 1-2 using HCl to giveS112a (96%), which was used for the next step without furtherpurification.

1-(2-Fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid (S112b)

The title compound was synthesized according to the same proceduredescribed for the synthesis of compound S112a (94%). ¹H-NMR (400 MHz,DMSO-d₆) δ 12.56 (s, 1H), 8.03 (s, 1H), 7.64-7.58 (m, 2H), 7.53-7.748(t, J=8.8 Hz, 1H), 7.43-7.39 (t, J=8.8 Hz, 1H), 2.37 (s, 3H); ¹³C-NMR(100 MHz, DMSO-d₆) δ 169.5, 162.9, 160.2, 149.9, 147.3, 136.9, 136.8,134.5, 130.5, 130.5, 122.0, 121.8, 117.9, 15.8.

1-(2-Chlorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid (S112c)

The title compound was synthesized according to the same proceduredescribed for the synthesis of compound S112a (90%). ¹H-NMR (400 MHz,DMSO-d₆) δ 12.38 (s, 1H), 8.00 (s, 1H), 7.75-7.73 (d, J=8.0 Hz, 1H),7.64-7.54 (m, 3H), 2.29 (s, 3H); ¹³C-NMR (100 MHz, DMSO-d₆) δ 169.6,149.8, 147.0, 141.0, 136.8, 136.3, 135.4, 135.2, 133.6, 117.5, 15.9.

1-(2-Bromophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid (S112d)

The title compound was synthesized according to the same proceduredescribed for the synthesis of compound S112a (98%).

5-Methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (S112e)

The title compound was synthesized according to the same proceduredescribed for the synthesis of compound S112a (80%). ¹H-NMR (400 MHz,DMSO-d₆) δ 12.45 (s, 1H), 7.98 (s, 1H), 7.59-7.49 (m, 5H), 2.51 (s, 3H);¹³C-NMR (100 MHz, DMSO-d₆) δ 169.7, 148.4, 146.8, 143.8, 134.5, 133.7,130.5, 118.2, 16.7.

1-(2,4-Difluorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid (S112f)

The title compound was synthesized according to the same proceduredescribed for the synthesis of compound S112a (83%). ¹H-NMR (400 MHz,DMSO-d₆) δ 12.49 (s, 1H), 8.01 (s, 1H), 7.72-7.66 (m, 1H), 7.62-7.56 (m,1H), 7.33-7.29 (m, 1H), 2.36 (s, 3H); ¹³C-NMR (100 MHz, DMSO-d₆) δ169.5, 168.9, 168.8, 166.4, 166.3, 163.3, 163.1, 160.7, 160.6, 150.2,147.4, 136.0, 135.9, 117.9, 117.8, 117.6, 117.6, 110.8, 110.5, 110.3,15.8.

1-(2,5-Dimethylphenyl)-5-methyl-1H-pyrazole-4-carboxylic acid (S112g)

The title compound was synthesized according to the same proceduredescribed for the synthesis of compound S112a (75%). ¹H-NMR (400 MHz,DMSO-d₆) δ 12.11 (s, 1H), 7.96 (s, 1H), 7.31-7.29 (d, J=8.0 Hz, 1H),7.26-7.24 (d, J=8.0 Hz, 1H), 7.13 (s, 1H), 2.32 (s, 3H), 2.26 (s, 3H),1.90 (s, 3H); ¹³C-NMR (100 MHz, DMSO-d₆) δ 169.8, 148.9, 146.4, 142.5,141.5, 137.3, 135.9, 135.5, 133.1, 117.1, 25.4, 21.4, 15.9.

1-(2-Ethylphenyl)-5-methyl-1H-pyrazole-4-carboxylic acid (S112h)

The title compound was synthesized according to the same proceduredescribed for the synthesis of compound S112a (78%). ¹H-NMR (400 MHz,DMSO-d₆) δ 12.41 (s, 1H), 7.98 (s, 1H), 7.53-7.47 (m, 2H), 7.40-7.36 (t,J=8.0 Hz, 1H), 7.32-7.30 (d, J=8.0 Hz, 1H), 2.29-2.67 (m, 5H), 1.00-0.96(t, J=8.0 Hz, 3H); ¹³C-NMR (100 MHz, DMSO-d₆) δ 169.7, 149.2, 146.4,146.4, 142.0, 135.1, 134.8, 132.9, 131.9, 117.1, 28.6, 19.6, 16.2.

1-(2,6-Dimethylphenyl)-5-methyl-1H-pyrazole-4-carboxylic acid (S112j)

The title compound was synthesized according to the same proceduredescribed for the synthesis of compound S112a (48%). ¹H-NMR (400 MHz,DMSO-d₆) δ 12.44 (s, 1H), 8.01 (s, 1H), 7.39-7.35 (t, J=8.0 Hz, 1H),7.27-7.25 (d, J=8.0 Hz, 1H), 2.20 (s, 3H), 1.88 (s, 6H); ¹³C-NMR (100MHz, DMSO-d₆) δ 169.8, 148.9, 146.9, 141.8, 141.0, 134.8, 133.5, 117.0,21.9, 15.4.

1-(3-Chloro-2-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid

The title compound was synthesized according to the same proceduredescribed for the synthesis of compound S112a (86%). ¹H-NMR (400 MHz,DMSO-d₆) δ 12.45 (s, 1H), 8.04 (s, 1H), 7.84-7.80 (t, J=7.2 Hz, 1H),7.63-7.59 (t, J=7.2 Hz, 1H), 7.46-7.42 (t, J=7.2 Hz, 1H), 2.38 (s, 3H);¹³C-NMR (100 MHz, DMSO-d₆) δ 169.4, 158.7, 156.1, 150.2, 147.6, 137.1,133.5, 132.6, 132.5, 131.0, 130.9, 126.2, 126.0, 118.1, 15.9.

1-(2-Bromophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid

The title compound was synthesized according to the same proceduredescribed for the synthesis of compound S112a (65%). ¹H-NMR (400 MHz,DMSO-d₆) δ 12.45 (s, 1H), 7.99 (s, 1H), 7.89-7.87 (d, J=8.0 Hz, 1H),7.61-7.54 (m, 3H), 2.28 (s, 3H); ¹³C-NMR (100 MHz, DMSO-d₆) δ 169.6,149.5, 146.8, 142.7, 138.5, 137.0, 135.2, 134.1, 126.6, 117.5, 16.0.

1-(Tert-butyl)-5-methyl-1H-pyrazole-4-carboxylic acid (S112i)

The title compound was synthesized according to the same proceduredescribed for the synthesis of compound S12a (40%). ¹H-NMR (400 MHz,DMSO-d₆) δ 12.16 (s, 1H), 7.68 (s, 1H), 2.69 (s, 3H), 1.59 (s, 9H);¹³C-NMR (100 MHz, DMSO-d₆) δ 170.1, 147.5, 143.7, 118.1, 65.8, 34.8,17.6.

5-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxylic acid

The title compound was synthesized according to the same proceduredescribed for the synthesis of compound S112a (62%). ¹H-NMR (400 MHz,DMSO-d₆) δ 12.42 (s, 1H), 7.86 (s, 1H), 5.21-5.16 (m, 2H), 2.54 (s, 3H);¹³C-NMR (100 MHz, DMSO-d₆) δ 169.4, 150.1, 146.8, 145.7, 117.8, 54.1,54.1, 15.1.

5-methyl-1-(1-phenylethyl)-1H-pyrazole-4-carboxylic acid

The title compound was synthesized according to the same proceduredescribed for the synthesis of compound S112a (58%). ¹H-NMR (400 MHz,DMSO-d₆) δ 12.26 (s, 1H), 7.84 (s, 1H), 7.34-7.30 (t, J=7.2 Hz, 2H),7.27-7.23 (t, J=7.2 Hz, 1H), 7.20-7.18 (d, J=7.2 Hz, 1H), 5.70-5.64 (q,J=7.2 Hz, 1H), 2.44 (s, 3H), 1.80-1.78 (d, J=7.2 Hz, 3H); ¹³C-NMR (100MHz, DMSO-d₆) δ 169.9, 147.7, 147.1, 145.3, 133.8, 132.6, 131.3, 117.0,61.9, 26.7, 15.1.

5-Methyl-1-(3-methylpyridin-2-yl)-1H-pyrazole-4-carboxylic acid

The title compound was synthesized according to the same proceduredescribed for the synthesis of compound S112a (48%). ¹H-NMR (400 MHz,DMSO-d₆) δ 12.27 (s, 1H), 8.47-8.46 (d, J=4.0 Hz, 1H), 7.99-7.96 (m,2H), 7.56-7.53 (m, 1H), 2.37 (s, 3H), 2.11 (s, 3H); ¹³C-NMR (100 MHz,DMSO-d₆) δ 169.6, 154.9, 151.7, 149.1, 146.6, 146.1, 135.8, 130.3,117.5, 21.8, 16.0.

5-Methyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-pyrazole-4-carboxamide (132)

The title compound was synthesized according to the same proceduredescribed for the synthesis of compound 5. White solid. Yield: 58%, 60mg. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.86 (s, 1H), 8.62 (s, 1H), 8.40-8.36(m, 2H), 7.95-7.93 (d, J=8.0 Hz, 1H), 7.90-7.88 (d, J=8.8 Hz, 1H),7.75-7.71 (t, J=7.2 Hz, 1H), 7.53-7.34 (m, 5H), 2.36 (s, 3H), 2.00 (s,3H); ¹³C-NMR (100 MHz, DMSO-d₆) δ 167.7, 157.3, 151.6, 149.2, 144.9,143.1, 142.7, 140.7, 136.2, 135.1, 134.9, 132.9, 132.8, 132.1, 132.0,130.8, 130.1, 120.6, 119.2, 21.9, 16.3. HRMS [M+H]⁺ (ESI-TOF) calcd forC₂₁H₁₉N₄O 343.1559, found 343.1588. HPLC: t_(R)=6.33 min, 99.8%.

1-(2-Fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide(133)

The title compound was synthesized according to the same proceduredescribed for the synthesis of compound 5. White solid. Yield: 82%, 85mg. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.93 (s, 1H), 8.64 (s, 1H), 8.39 (m,2H). 7.96-7.94 (d, J=8.0 Hz, 1H), 7.90-7.88 (d, J=8.0 Hz, 1H), 7.55-7.71(t, J=8.0 Hz, 1H), 7.65-7.61 (m, 2H), 7.57-7.50 (m, 2H), 7.46-7.42 (t,J=8.0 Hz, 1H), 2.46 (s, 3H); ¹³C-NMR (100 MHz, DMSO-d₆) δ 167.5, 162.7,160.2, 157.2, 151.6, 150.1, 145.8, 145.6, 143.1, 136.9, 136.8, 135.1,134.6, 132.9, 132.1, 130.9, 130.6, 130.1, 122.0, 121.9, 120.6, 119.8,16.2. HRMS [M+H]⁺ (ESI-TOF) calcd for C₂₀H₁₆FN₄O 347.1308, found347.1300. HPLC: t_(R)=5.83 min, 99.7%.

1-(2-Chlorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide(135)

The title compound was synthesized according to the same proceduredescribed for the synthesis of compound 5. White solid. Yield: 64%, 70mg. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.91 (s, 1H), 8.65 (s, 1H), 8.39 (m,2H), 7.96-7.94 (d, J=8.8 Hz, 1H), 7.90-7.88 (d, J=8.8 Hz, 1H), 7.78-7.74(m, 2H), 7.64-7.59 (m, 3H), 7.54-7.50 (t, J=8.0 Hz, 1H), 2.39 (s, 3H);¹³C-NMR (100 MHz, DMSO-d₆) δ 167.5, 157.2, 151.6, 150.0, 145.4, 143.1,141.1, 136.8, 136.3, 135.5, 135.2, 135.1, 133.6, 132.9, 132.1, 130.9,130.1, 120.6, 119.5, 16.2. HRMS [M+H]⁺ (ESI-TOF) calcd for C₂₀H₁₆ClN₄O363.1013, found 363.1015. HPLC: t_(R)=6.96 min, 99.6%.

1-(2-Ethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide(136)

The title compound was synthesized according to the same proceduredescribed for the synthesis of compound 5. Brown solid. Yield: 84%, 90mg. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.85 (s, 1H), 8.62 (s, 1H), 8.39 (m,2H), 7.96-7.94 (d, J=8.0 Hz, 1H), 7.90-7.88 (d, J=8.0 Hz, 1H), 7.55-7.71(t, J=8.0 Hz, 1H), 7.53-7.50 (m, 3H), 7.42-7.38 (t, J=8.0 Hz, 1H),7.34-7.32 (d, J=8.0 Hz, 1H), 2.36-2.31 (m, 5H), 1.03-1.0 (q, J=8.0 Hz,3H); ¹³C-NMR (100 MHz, DMSO-d₆) δ 167.7, 157.2, 151.6, 149.4, 146.5,144.7, 143.1, 142.1, 135.2, 135.1, 134.8, 133.0, 132.9, 132.1, 131.9,130.8, 130.1, 120.6, 119.1, 28.6, 19.7, 16.5. HRMS [M+H]⁺ (ESI-TOF)calcd for C₂₂H₂₁N₄O 357.1715, found 357.1715. HPLC: t_(R)=9.03 min,99.2%.

1-(2,6-dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide(137)

The title compound was synthesized according to the same proceduredescribed for the synthesis of compound 5. Yellow foam. Yield: 74%, 80mg. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.85 (s, 1H), 8.67 (s, 1H), 8.39 (m,2H), 7.96-7.94 (d, J=8.0 Hz, 1H), 7.90-7.88 (d, J=8.0 Hz, 1H), 7.76-7.72(t, J=8.0 Hz, 1H), 7.54-7.50 (t, J=8.0 Hz, 1H), 7.40-7.36 (t, J=8.0 Hz,1H), 7.29-7.27 (m, 2H), 2.29 (s, 3H), 1.91 (s, 6H); ¹³C-NMR (100 MHz,DMSO-d₆) δ 167.7, 157.2, 151.6, 149.1, 145.2, 143.1, 141.8, 141.1,135.1, 134.8, 133.5, 132.9, 132.1, 130.8, 130.1, 120.6, 119.1, 21.9,15.8. HRMS [M+H]⁺ (ESI-TOF) calcd for C₂₂H₂₁N₄O 357.1715, found357.1714. HPLC: t_(R)=7.82 min, 99.6%.

1-(Tert-butyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide(138)

The title compound was synthesized according to the same proceduredescribed for the synthesis of compound 5. White solid. Yield: 57%, 53mg. ¹H-NMR (400 MHz, DMSO-d₆) δ 10.73 (s, 1H), 8.43 (s, 2H), 8.34 (s,1H), 8.02-8.00 (d, J=8.0 Hz, 1H), 7.95-7.93 (d, J=8.0 Hz, 1H), 7.82-7.78(t, J=8.0 Hz, 1H), 7.60-7.56 (t, J=8.0 Hz, 1H), 2.86 (s, 3H), 1.71 (s,9H); ¹³C-NMR (100 MHz, DMSO-d₆) 168.2, 157.3, 151.6, 147.4, 142.9,142.1, 135.0, 132.9, 132.0, 130.8, 130.0, 120.6, 120.3, 65.8, 34.8,18.0. HRMS [M+H]⁺ (ESI-TOF) calcd for C₁₈H₂₁N₄O 309.1715, found309.1722. HPLC: t_(R)=5.08 min, 96.2%.

1-(2,5-dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide(139)

Yellow oil. Yield: 56%, 60 mg. ¹H-NMR (400 MHz, CDCl₃) δ 8.84 (s, 1H),8.56-8.54 (d, J=8.8 Hz, 1H), 8.20-8.18 (d, J=8.8 Hz, 1H), 8.11 (s, 1H),7.84-7.82 (d, J=8.8 Hz, 1H), 7.79-7.77 (d, J=8.8 Hz, 1H), 7.68-7.64 (t,J=8.0 Hz, 1H), 7.46-7.42 (t, J=8.0 Hz, 1H), 7.21-7.18 (m, 2H), 7.04 (s,1H), 2.45 (s, 3H), 2.35 (s, 3H), 1.98 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃)δ 162.4, 151.3, 146.4, 144.4, 138.6, 138.4, 137.3, 136.7, 132.5, 130.9,130.6, 130.0, 127.6, 127.1, 126.2, 125.1, 114.6, 114.4, 20.7, 16.7,11.3. HRMS [M+H]⁺ (ESI-TOF) calcd for C₂₂H₂₁N₄O 357.1715, found357.1728. HPLC: t_(R)=8.39 min, 99.9%.

1-(2,4-difluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide(140)

Brown solid. Yield: 82%, 89 mg. ¹H-NMR (400 MHz, CDCl₃) δ 8.75 (s, 1H),8.54-8.52 (d, J=8.8 Hz, 1H), 8.22-8.20 (d, J=8.8 Hz, 1H), 8.14 (s, 1H),7.84-7.82 (d, J=8.8 Hz, 1H), 7.81-7.79 (d, J=8.8 Hz, 1H), 7.69-7.65 (t,J=8.8 Hz, 1H), 7.50-7.44 (m, 2H), 7.06-7.02 (m, 2H), 2.55 (s, 3H);¹³C-NMR (100 MHz, CDCl₃) δ 164.4, 164.3, 161.9, 158.4, 155.7, 151.1,146.4, 145.6, 139.4, 138.7, 130.1, 130.0, 127.6, 127.0, 126.3, 125.2,115.2, 114.5, 112.4, 112.2, 105.4, 105.2, 104.9, 11.2. HRMS [M+H]⁺(ESI-TOF) calcd for C₂₀H₁₅F₂N₄O 365.1214, found 365.1202. HPLC:t_(R)=6.07 min, 99.8%.

5-methyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide (141)

Yellow solid. Yield: 81%, 80 mg. ¹H-NMR (400 MHz, CDCl₃) δ 8.74 (s, 1H),8.55-8.53 (d, J=9.6 Hz, 1H), 8.20-8.18 (d, J=9.6 Hz, 1H), 8.09 (s, 1H),7.84-7.82 (d, J=8.8 Hz, 1H), 7.79-0.77 (d, J=8.0 Hz, 1H), 7.68-7.64 (t,J=8.0 Hz, 1H), 7.53-7.49 (m, 2H), 7.47-7.43 (m, 4H), 2.66 (s, 3H);¹³C-NMR (100 MHz, CDCl₃) δ 162.2, 151.2, 146.4, 143.6, 138.6, 138.4,130.1, 129.3, 128.8, 127.6, 127.0, 126.3, 125.5, 125.1, 115.4, 114.5,12.1. HRMS [M+H]⁺ (ESI-TOF) calcd for C₂₀H₁₇N₄O 329.1402, found329.1409. HPLC: t_(R)=5.45 min, 99.9%.

1-(2-bromophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide(134)

Yellow solid. Yield: 65%, 80 mg. ¹H-NMR (400 MHz, CDCl₃) δ 8.74 (s, 1H),8.55-8.53 (d, J=8.0 Hz, 1H), 8.20-8.18 (d, J=8.8 Hz, 1H), 8.11 (s, 1H),7.84-7.82 (d, J=8.8 Hz, 1H), 7.79-7.77 (d, J=8.8 Hz, 1H), 7.74-7.72 (d,J=8.8 Hz, 1H), 7.68-7.64 (t, J=8.0 Hz, 1H), 7.49-7.44 (m, 2H), 7.42-7.37(m, 2H), 2.50 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ 162.1, 151.2, 146.6,145.2, 138.8, 138.5, 137.8, 133.6, 131.4, 130.0, 129.6, 128.4, 127.6,127.2, 126.3, 125.1, 122.3, 114.8, 114.5, 11.4. HRMS [M+H]⁺ (ESI-TOF)calcd for C₂₀H₁₅BrN₄O 407.0507, found 407.0513. HPLC: t_(R)=7.11 min,97.6%.

1-cyclohexyl-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide (142)

Light yellow solid. Yield: 60%, 60 mg. ¹H-NMR (400 MHz, CDCl₃) δ 8.71(s, 1H), 8.51-8.49 (d, J=8.4 Hz, 1H), 8.16-8.14 (d, J=9.6 Hz, 1H), 7.93(s, 1H), 7.80-7.78 (d, J=8.8 Hz, 1H), 7.76-7.74 (d, J=8.0 Hz, 1H),7.65-7.61 (t, J=8.0 Hz, 1H), 7.43-7.39 (t, J=8.0 Hz, 1H), 4.06-4.01 (m,1H), 2.64 (s, 3H), 1.96-1.74 (m, 6H), 1.44-1.21 (m, 4H); ¹³C-NMR (100MHz, CDCl₃) δ 162.6, 151.4, 146.4, 141.8, 138.5, 137.2, 129.9, 127.5,127.0, 126.2, 124.9, 114.5, 113.9, 57.7, 32.5, 25.6, 25.1, 10.4. HRMS[M+H]⁺ (ESI-TOF) calcd for C₂₀H₂₂N₄O 335.1872, found 335.1871. HPLC:t_(R)=5.73 min, 99.2%.

5-methyl-1-(1-phenylethyl)-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide(143)

Off-white solid. Yield: 70%, 75 mg. ¹H-NMR (400 MHz, CDCl₃) δ 8.51 (s,1H), 8.49 (s, 1H), 8.19-8.17 (d, J=8.4 Hz, 1H), 7.98 (s, 1H), 7.84-7.82(d, J=8.8 Hz, 1H), 7.79-7.77 (d, J=8.0 Hz, 1H), 7.69-7.65 (t, J=8.0 Hz,1H), 7.47-7.43 (t, J=8.0 Hz, 1H), 7.35-7.31 (t, J=7.2 Hz, 2H), 7.29-7.27(d, J=7.2 Hz, 1H), 7.17-7.15 (d, J=7.2 Hz, 2H), 5.52-5.47 (q, J=6.8 Hz,1H), 2.57 (s, 3H), 1.97-1.95 (d, J=6.8 Hz, 3H); ¹³C-NMR (100 MHz, CDCl₃)δ 162.4, 151.2, 146.6, 143.0, 141.4, 138.5, 137.1, 130.0, 128.8, 127.8,127.6, 127.1, 126.3, 125.9, 125.0, 114.7, 114.5, 58.1, 21.6, 10.6. HRMS[M+H]⁺ (ESI-TOF) calcd for C₂₂H₂₁N₄O 357.1715, found 357.1709. HPLC:t_(R)=7.72 min, 99.8%.

5-methyl-N-(quinolin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide(144)

White solid. Yield: 35%, 35 mg. ¹H-NMR (400 MHz, CDCl₃) δ 8.80 (s, 1H),8.50-8.48 (d, J=8.4 Hz, 1H), 8.21-8.18 (d, J=9.6 Hz, 1H), 8.02 (s, 1H),7.83-7.81 (d, J=9.6 Hz, 1H), 7.80-7.78 (d, J=8.4 Hz, 1H), 7.69-7.65 (t,J=7.2 Hz, 1H), 7.48-7.44 (t, J=7.2 Hz, 1H), 4.75-4.69 (q, J=8.8 Hz, 2H),2.69 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ 162.2, 151.1, 146.4, 144.9,139.0, 138.7, 138.4, 130.1, 127.6, 126.9, 126.3, 125.2, 124.2, 115.6,114.5, 50.4, 50.3, 50.0, 49.6, 10.6. HRMS [M+H]⁺ (ESI-TOF) calcd forC₁₆H₁₄F₃N₄O 335.1120, found 335.1120. HPLC: t_(R)=4.51 min, 96.0%.

5-methyl-1-(3-methylpyridin-2-yl)-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide(145)

White solid. Yield: 24%, 25 mg. ¹H-NMR (400 MHz, CDCl₃) δ 8.55 (s, 1H),8.53 (s, 1H), 8.47-8.46 (d, J=4.0 Hz, 1H), 8.21-8.19 (d, J=8.8 Hz, 1H),8.01 (s, 1H), 7.85-7.83 (d, J=8.0 Hz, 1H), 7.81-7.79 (d, J=8.0 Hz, 1H),7.77-7.75 (d, J=8.0 Hz, 1H), 7.70-7.66 (t, J=8.0 Hz, 1H), 7.47-7.43 (t,J=8.0 Hz, 1H), 7.39-7.36 (m, 1H), 2.58 (s, 3H), 2.20 (s, 3H); ¹³C-NMR(100 MHz, CDCl₃) δ 162.1, 151.1, 150.0, 146.7, 144.7, 140.6, 138.5,131.0, 130.0, 127.6, 127.3, 126.3, 125.1, 124.8, 114.9, 114.5, 17.2,11.4. HRMS [M+H]⁺ (ESI-TOF) calcd for C₂₀H₁₈N₅O 344.1511, found344.1507. HPLC: t_(R)=3.73 min, 99.6%.

1-(3-chloro-2-fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide(146)

White solid. Yield: 56%, 60 mg. ¹H-NMR (400 MHz, CDCl₃) δ 8.70 (s, 1H),8.54-8.52 (d, J=8.4 Hz, 1H), 8.22-8.20 (d, J=8.8 Hz, 1H), 8.14 (s, 1H),7.84-7.82 (d, J=8.8 Hz, 1H), 7.81-7.79 (d, J=8.0 Hz, 1H), 7.69-7.65 (t,J=7.2 Hz, 1H), 7.58-7.54 (t, J=7.2 Hz, 1H), 7.48-7.44 (t, J=7.2 Hz, 1H),7.41-7.37 (t, J=7.2 Hz, 1H), 7.28-7.24 (t, J=8.0 Hz, 1H), 2.58 (s, 3H);¹³C-NMR (100 MHz, CDCl₃) δ 161.8, 154.2, 151.6, 151.1, 146.5, 145.6,139.5, 138.6, 131.8, 130.1, 127.6, 127.3, 127.2, 126.3, 125.2, 124.9,124.8, 122.7, 115.4, 114.5, 11.3. HRMS [M+H]⁺ (ESI-TOF) calcd forC₂₀H₁₅ClFN₄O 381.0918, found 381.0928. HPLC: t_(R)=10.21 min, 99.8%.

1-(2,6-difluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide(147)

Yellow foam. Yield: 64%, 70 mg. ¹H-NMR (400 MHz, CDCl₃) δ 8.91 (s, 1H),8.53-8.51 (d, J=9.6 Hz, 1H), 8.18 (s, 1H), 8.18-8.16 (d, J=8.8 Hz, 1H),7.82-7.80 (d, J=8.4 Hz, 1H), 7.77-7.75 (d, J=8.0 Hz, 1H), 7.65-7.61 (t,J=7.2 Hz, 1H), 7.48-7.40 (m, 2H), 7.11-7.07 (t, J=8.0 Hz, 1H), 2.53 (s,3H); ¹³C-NMR (100 MHz, CDCl₃) δ 161.9, 159.6, 157.1, 157.0, 151.2,146.4, 139.9, 138.6, 131.6, 131.5, 131.4, 130.0, 127.6, 127.1, 126.3,125.1, 115.2, 114.6, 112.5, 112.3, 10.9. HRMS [M+H]⁺ (ESI-TOF) calcd forC₂₀H₁₅F₂N₄O 365.1214, found 365.1210. HPLC: t_(R)=7.08 min, 99.5%.

1-(2-bromo-6-fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide(148)

White solid. Yield: 69%, 87 mg. ¹H-NMR (400 MHz, CDCl₃) δ 8.89 (s, 1H),8.55-8.53 (d, J=8.8 Hz, 1H), 8.20-8.18 (t, J=4.8 Hz, 2H), 7.83-7.81 (d,J=8.0 Hz, 1H), 7.78-7.76 (d, J=8.8 Hz, 1H), 7.67-7.63 (t, J=8.0 Hz, 1H),7.54-7.52 (d, J=8.0 Hz, 1H), 7.45-7.41 (t, J=8.0 Hz, 1H), 7.40-7.35 (m,1H), 7.25-7.21 (t, J=8.0 Hz, 1H), 2.50 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃)δ 161.9, 160.2, 157.6, 151.2, 146.5, 145.9, 139.7, 138.6, 132.3, 132.2,130.1, 128.9, 127.6, 127.1, 126.5, 126.3, 125.1, 123.9, 115.9, 115.8,115.1, 114.6, 10.9. HRMS [M+H]⁺ (ESI-TOF) calcd for C₂₀H₁₅BrFN₄O425.0413, found 425.0416. HPLC: t_(R)=9.03 min, 99.9%.

(Z)-ethyl 2-chloro-2-(2-phenylhydrazono)acetate

Yellow solid. Yield: 95%. ¹H-NMR (400 MHz, CDCl₃) δ 8.40 (s, 1H),7.35-7.31 (t, J=8.0 Hz, 2H), 7.24-7.22 (d, J=8.0 Hz, 2H), 7.06-7.02 (t,J=8.0 Hz, 1H), 4.41-4.36 (q, J=7.2 Hz, 2H), 1.42-1.38 (t, J=7.2 Hz, 3H);¹³C-NMR (100 MHz, CDCl₃) δ 159.7, 141.6, 129.4, 123.1, 115.9, 114.5,62.8, 14.2.

(Z)-ethyl 2-chloro-2-(2-(o-tolyl)hydrazono)acetate

Yellow solid. Yield: 88%. ¹H-NMR (400 MHz, CDCl₃) δ 8.27 (s, 1H),7.56-7.54 (d, J=8.0 Hz, 1H), 7.26-7.22 (t, J=8.0 Hz, 1H), 7.26-7.22 (t,J=8.0 Hz, 1H), 7.15-7.13 (d, J=8.0 Hz, 1H), 4.43-4.37 (q, J=7.2 Hz, 2H),2.31 (s, 3H), 1.43-1.39 (t, J=7.2 Hz, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ159.7, 139.4, 130.7, 127.4, 122.8, 122.3, 116.8, 114.5, 62.8, 16.7,14.2.

(Z)-ethyl 2-chloro-2-(2-(2-ethylphenyl)hydrazono)acetate

Yellow solid. Yield: 90%. ¹H-NMR (400 MHz, CDCl₃) δ 8.39 (s, 1H),7.58-7.56 (d, J=8.0 Hz, 1H), 7.26-7.22 (t, J=8.0 Hz, 1H), 7.17-7.15 (d,J=8.0 Hz, 1H), 7.03-6.99 (t, J=8.0 Hz, 1H), 4.42-4.37 (q, J=7.2 Hz, 2H),2.68-2.62 (q, J=8.0 Hz, 2H), 1.43-1.39 (t, J=7.2 Hz, 3H), 1.32-1.28 (t,J=8.0 Hz, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ 159.7, 138.8, 128.7, 128.3,127.4, 123.1, 116.6, 114.9, 62.7, 23.6, 14.2, 13.4.

5-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid

Yellow solid. Yield: 85% for two steps. ¹H-NMR (400 MHz, CDCl₃) δ7.51-7.47 m, 5H), 6.79 (s, 1H), 2.34 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃)δ166.3, 142.8, 141.0, 138.9, 129.2, 128.8, 125.3, 109.6, 12.4.

5-methyl-1-(o-tolyl)-1H-pyrazole-3-carboxylic acid

White solid. Yield: 80% for two steps. ¹H-NMR (400 MHz, CDCl₃) δ7.41-7.38 (t, J=6.8 Hz, 1H), 7.34-7.32 (d, J=8.4 Hz, 1H), 7.30-7.28 (d,J=8.4 Hz, 1H), 7.26-7.22 (t, J=6.8 Hz, 1H), 6.79 (s, 1H), 2.13 (s, 3H),2.04 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ 166.1, 142.7, 141.9, 137.7,135.8, 131.0, 129.9, 127.5, 126.6, 108.2, 17.1, 11.4.

1-(2-ethylphenyl)-5-methyl-1H-pyrazole-3-carboxylic acid

Yellow solid. Yield: 70% for two steps. ¹H-NMR (400 MHz, CDCl₃) δ7.47-7.43 (t, J=6.8 Hz, 1H), 7.40-7.38 (d, J=6.8. Hz, 1H), 7.33-7.29 (d,J=6.8 Hz, 1H), 7.22-7.02 (d, J=7.6 Hz, 1H), 6.79 (s, 1H), 2.38-2.33 (q,J=7.2 Hz, 2H), 2.14 (s, 3H), 1.10-1.06 (t, J=7.2 Hz, 3H); ¹³C-NMR (100MHz, CDCl₃) δ 165.8, 142.6, 142.1, 141.6, 137.1, 130.1, 129.4, 127.6,126.6, 108.2, 23.8, 14.3, 11.5.

5-methyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-3-carboxamide (149)

White solid. Yield: 71%, 70 mg. ¹H-NMR (400 MHz, CDCl₃) δ 9.65 (s, 1H),8.62-8.60 (d, J=9.6 Hz, 1H), 8.21-8.18 (d, J=9.6 Hz, 1H), 7.86-7.84 (d,J=8.4 Hz, 1H), 7.79-7.77 (d, J=8.8 Hz, 1H), 7.67-7.63 (t, J=7.2 Hz, 1H),7.56-7.41 (m, 6H), 6.86 (s, 1H), 2.39 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃)δ 160.6, 150.9, 146.8, 146.1, 141.4, 139.1, 138.4, 129.8, 129.2, 128.6,127.5, 127.4, 126.3, 125.0, 124.9, 114.4, 107.8, 12.6. HRMS [M+H]⁺(ESI-TOF) calcd for C₂₀H₁₇N₄O 329.1402, found 329.1406. HPLC:t_(R)=20.42 min, 99.9%.

5-methyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-pyrazole-3-carboxamide (150)

White solid. Yield: 68%, 70 mg. ¹H-NMR (400 MHz, CDCl₃) δ 9.63 (s, 1H),8.61-8.59 (d, J=9.6 Hz, 1H), 8.19-8.17 (d, J=9.6 Hz, 1H), 7.82-7.80 (d,J=8.8 Hz, 1H), 7.78-7.76 (d, J=8.0 Hz, 1H), 7.65-7.61 (t, J=7.2 Hz, 1H),7.45-7.28 (m, 4H), 7.28-7.26 (d, J=7.2 Hz, 1H), 6.86 (s, 1H), 2.16 (s,3H), 2.08 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ 160.7, 150.9, 146.9,146.1, 142.2, 138.3, 137.8, 135.9, 131.2, 129.8, 129.7, 127.5, 127.4,127.4, 126.8, 126.2, 124.9, 114.3, 106.3, 17.2, 11.5. HRMS [M+H]⁺(ESI-TOF) calcd for C₂₁H₁₉N₄O 343.1559, found 343.1558. HPLC: t_(R)=8.54min, 99.9%.

1-(2-ethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-3-carboxamide(151)

Yellow solid. Yield: 66%, 70 mg. ¹H-NMR (400 MHz, CDCl₃) δ 9.63 (s, 1H),8.62-8.60 (d, J=8.8 Hz, 1H), 8.19-8.17 (d, J=8.8 Hz, 1H), 7.8-7.80 (d,J=8.8 Hz, 1H), 7.77-7.75 (d, J=8.0 Hz, 1H), 7.64-7.60 (t, J=7.2 Hz, 1H),7.50-7.39 (m, 3H), 7.37-7.33 (t, J=7.6 Hz, 1H), 7.25-7.23 (d, J=8.0 Hz,1H), 6.86 (s, 1H), 2.44-2.40 (t, J=8.0 Hz, 2H), 2.15 (s, 3H), 1.13-1.09(d, J=8.0 Hz, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ 160.7, 150.9, 146.9,146.0, 142.4, 141.7, 138.3, 137.3, 130.1, 129.8, 129.6, 127.6, 127.5,126.7, 126.2, 124.9, 114.3, 106.3, 23.9, 14.5, 11.6. HRMS [M+H]⁺(ESI-TOF) calcd for C₂₂H₂₁N₄O 357.1715, found 357.1717. HPLC:t_(R)=11.11 min, 99.7%.

1-phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxylic acid

Brown solid. Yield: 78% for two steps. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.57(s, 1H), 7.54-7.52 (d, J=8.0 Hz, 2H), 7.37-7.33 (t, J=8.0 Hz, 2H),7.21-7.17 (t, J=8.0 Hz, 1H), 2.89-2.85 (t, J=7.2 Hz, 2H), 2.57-2.53 (t,J=7.2 Hz, 2H), 2.42-2.34 (m, 2H); ¹³C-NMR (100 MHz, DMSO-d₆) δ 168.3,155.2, 144.4, 143.3, 136.7, 134.6, 131.9, 124.5, 35.3, 30.9, 28.4.

1-phenyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid

Brown solid. Yield: 65% for two steps. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.67(s, 1H), 7.59-7.54 (m, 4H), 7.46-7.42 (t, J=7.2 Hz, 1H), 2.70 (m, 4H),1.72 (m, 4H); ¹³C-NMR (100 MHz, DMSO-d₆) δ 169.0, 146.1, 145.3, 144.2,134.5, 132.9, 128.6, 125.3, 28.0, 27.3, 27.2, 26.7.

1-phenyl-N-(quinolin-2-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxamide(152)

White solid. Yield: 63%, 66 mg. ¹H-NMR (400 MHz, CDCl₃) δ 9.62 (s, 1H),8.63-8.51 (d, J=9.6 Hz, 1H), 8.19-8.17 (d, J=8.8 Hz, 1H), 7.90-7.88 (d,J=8.4 Hz, 1H), 7.79-7.77 (d, J=8.0 Hz, 1H), 7.75-7.7.73 (d, J=8.0 Hz,1H), 7.69-7.65 (t, J=8.0 Hz, 1H), 7.50-7.42 (m, 3H), 7.34-7.30 (t, J=8.0Hz, 1H), 3.05-3.01 (t, J=7.2 Hz, 2H), 2.98-2.94 (t, J=7.2 Hz, 2H),2.71-2.66 (m, 2H); ¹³C-NMR (100 MHz, CDCl₃) δ 160.9, 151.0, 150.9,146.8, 139.9, 139.7, 138.4, 131.5, 129.9, 129.4, 127.5, 127.4, 126.8,126.3, 124.9, 119.5, 114.3, 31.0, 26.8, 23.5. HRMS [M+H]⁺ (ESI-TOF)calcd for C₂₂H₁₉N₄O 355.1559, found 355.1564. HPLC: t_(R)=13.14 min,99.8%.

1-phenyl-N-(quinolin-2-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide(153)

White solid. Yield: 65%, 70 mg. ¹H-NMR (400 MHz, CDCl₃) δ 9.69 (s, 1H),8.63-8.61 (d, J=8.8 Hz, 1H), 8.18-8.16 (d, J=8.8 Hz, 1H), 7.87-7.85 (d,J=8.8 Hz, 1H), 7.77-7.75 (d, J=8.0 Hz, 1H), 7.66-7.64 (d, J=8.0 Hz, 1H),7.67-7.63 (t, J=8.0 Hz, 1H), 7.57-7.55 (d, J=8.0 Hz, 2H), 7.52-7.48 (t,J=8.0 Hz, 2H), 7.43-7.40 (m, 2H), 2.97 (m, 2H), 2.73 (m, 2H), 1.82 (m,4H); ¹³C-NMR (100 MHz, CDCl₃) δ 161.6, 151.1, 146.9, 142.4, 140.9,139.2, 138.3, 129.8, 129.2, 127.7, 127.5, 127.4, 126.2, 124.8, 123.5,120.6, 114.3, 23.8, 22.6, 22.4, 21.6. HRMS [M+H]⁺ (ESI-TOF) calcd forC₂₃H₂₁N₄O 369.1715, found 369.1717. HPLC: t_(R)=14.85 min, 99.9%.

Ethyl 3,5-dimethyl-1-phenyl-1H-pyrazole-4-carboxylate

Orange solid. Yield: 35%. ¹H-NMR (400 MHz, CDCl₃) δ 7.25-7.21 (t, J=8.0Hz, 2H), 7.18-7.13 (m, 3H), 4.11-4.05 (q, J=7.2 Hz, 2H), 2.27 (s, 3H),2.25 (s, 3H), 1.15-1.11 (t, J=7.2 Hz, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ164.4, 151.2, 144.3, 138.6, 128.9, 128.6, 128.2, 125.4, 121.6, 110.6,59.5, 14.2, 14.1, 12.4.

3,5-dimethyl-1-phenyl-1H-pyrazole-4-carboxylic acid

Off-white solid. Yield: 98%. ¹H-NMR (400 MHz, CDCl₃) δ 7.52-7.48 (t,J=8.0 Hz, 2H), 7.46-7.41 (m, 3H), 2.56 (s, 3H), 2.55 (s, 3H); ¹³C-NMR(100 MHz, CDCl₃) δ 170.2, 152.4, 145.7, 138.6, 129.2, 128.6, 125.7,110.0, 14.3, 12.7.

Ethyl 1-(2,5-dimethylphenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylate

White solid. Yield: 1 g. ¹H-NMR (400 MHz, CDCl₃) δ 7.21-7.16 (m, 2H),7.01 (s, 1H), 4.35-4.29 (q, J=7.2 Hz, 2H), 2.49 (s, 3H), 2.34 (s, 3H),2.30 (s, 3H), 1.98 (s, 3H), 1.40-4.36 (t, J=7.2 Hz, 3H); ¹³C-NMR (100MHz, CDCl₃) δ 164.7, 151.2, 145.3, 137.4, 136.6, 132.6, 130.7, 130.3,128.2, 110.8, 59.6, 20.7, 16.7, 14.4, 14.3, 11.8.

1-(2,5-dimethylphenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid

Yellow solid. Yield: 98%. ¹H-NMR (400 MHz, DMSO-d₆) δ 7.29-7.27 (d,J=8.0 Hz, 1H), 7.25-7.23 (d, J=8.0 Hz, 1H), 7.09 (s, 1H), 2.35 (s, 3H),2.31 (s, 3H), 2.21 (s, 3H), 1.90 (s, 3H); ¹³C-NMR (100 MHz, DMSO-d₆) δ170.6, 155.1, 149.7, 142.5, 141.4, 137.3, 135.8, 135.3, 133.2, 114.8,25.4, 21.5, 19.2, 16.7.

1-(2-bromophenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid

Yellow oil. Yield: 40%. ¹H-NMR (400 MHz, DMSO-d₆) δ 12.42 (s, 1H),7.87-7.85 (d, J=8.0 Hz, 1H), 7.60-7.49 (m, 3H), 2.36 (s, 3H), 2.24 (s,3H); ¹³C-NMR (100 MHz, DMSO-d₆) δ 170.3, 155.5, 150.4, 142.7, 138.4,136.8, 135.3, 134.1, 126.7, 115.1, 19.2, 16.

3,5-dimethyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide (154)

White foam. Yield: 68%, 70 mg. ¹H-NMR (400 MHz, CDCl₃) δ 8.70 (br, 1H),8.53-8.50 (d, J=8.8 Hz, 1H), 8.20-8.18 (d, J=8.8 Hz, 1H), 7.83-7.81 (d,J=8.8 Hz, 1H), 7.78-7.76 (d, J=8.8 Hz, 1H), 7.66-7.62 (t, J=8.0 Hz, 1H),7.50-7.37 (m, 6H), 2.65 (s, 3H), 2.56 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃)δ 163.4, 151.3, 147.8, 146.6, 142.8, 138.5, 129.9, 129.2, 128.6, 127.6,127.2, 126.3, 125.6, 125.1, 114.8, 114.6, 14.2, 12.5. HRMS [M+H]⁺(ESI-TOF) calcd for C₂₁H₁₉N₄O 343.1559, found 343.1556. HPLC: t_(R)=7.96min, 99.8%.

1-(2,5-dimethylphenyl)-3,5-dimethyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide(155)

Yellow solid. Yield: 64%, 71 mg. ¹H-NMR (400 MHz, CDCl₃) δ 8.44-8.42 (d,J=8.8 Hz, 1H), 8.39 (s, 1H), 8.11-8.09 (d, J=8.8 Hz, 1H), 7.75-7.73 (d,J=8.8 Hz, 1H), 7.70-7.68 (d, J=8.8 Hz, 1H), 7.58-7.54 (t, J=8.0 Hz, 1H),7.36-7.32 (t, J=7.2 Hz, 1H), 7.13-7.09 (m, 2H), 6.90 (s, 1H), 2.58 (s,3H), 2.29 (s, 3H), 2.25 (s, 3H), 1.91 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃)δ 163.3, 151.3, 147.5, 146.8, 143.8, 138.4, 137.2, 136.7, 132.5, 130.8,130.4, 129.9, 128.1, 127.6, 127.3, 126.3, 125.0, 114.6, 113.3, 20.7,16.7, 14.4, 11.8. HRMS [M+H]⁺ (ESI-TOF) calcd for C₂₃H₂₂N₄O 371.1872,found 371.1871. HPLC: t_(R)=9.03 min, 99.9%.

1-(2-bromophenyl)-3,5-dimethyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide(156)

White foam. Yield: 61%, 77 mg. ¹H-NMR (400 MHz, CDCl₃) δ 8.52-8.50 (d,J=8.8 Hz, 1H), 8.47 (br, 1H), 8.20-8.18 (d, J=9.6 Hz, 1H), 7.84-7.82 (d,J=8.8 Hz, 1H), 7.79-7.77 (d, J=8.0 Hz, 1H), 7.73-7.71 (d, J=8.0 Hz, 1H),7.67-7.63 (t, J=7.2 Hz, 1H), 7.47-7.42 (m, 2H), 7.38-7.34 (m, 2H), 2.67(s, 3H), 2.43 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ 163.1, 151.2, 148.2,146.7, 144.4, 138.5, 137.8, 133.5, 131.2, 129.9, 129.8, 128.5, 127.6,127.3, 126.3, 125.1, 122.4, 114.6, 113.9, 14.4, 11.9. HRMS [M+H]⁺(ESI-TOF) calcd for C₂₁H₁₈BrN₄O 421.0664, found 421.0670. HPLC:t_(R)=4.89 min, 99.0%.

5-ethyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide (157)

White solid. Yield: 66%, 68 mg. ¹H-NMR (400 MHz, CDCl₃) δ 8.66 (s, 1H),8.55-8.53 (d, J=9.6 Hz, 1H), 8.20-8.18 (d, J=9.6 Hz, 1H), 8.06 (s, 1H),7.85-7.83 (d, J=8.4 Hz, 1H), 7.80-7.78 (d, J=8.0 Hz, 1H), 7.69-7.65 (t,J=8.0 Hz, 1H), 7.54-7.43 (m, 6H), 3.09-3.04 (q, J=8.0 Hz, 2H), 1.25-1.21(t, J=8.0 Hz, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ 161.8, 151.2, 149.6,146.7, 138.8, 138.5, 138.5, 130.0, 129.3, 129.1, 127.6, 127.2, 126.3,125.9, 125.1, 114.5, 18.7, 13.7. HRMS [M+H]⁺ (ESI-TOF) calcd forC₂₁H₁₉N₄O 343.1559, found 343.1558. HPLC: t_(R)=3.63 min, 95.0%.

5-isopropyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide (158)

White solid. Yield: 56%, 60 mg. ¹H-NMR (400 MHz, CDCl₃) δ 8.83 (s, 1H),8.55-8.53 (d, J=8.4 Hz, 1H), 8.19-8.17 (d, J=8.8 Hz, 1H), 8.00 (s, 1H),7.83-7.81 (d, J=8.8 Hz, 1H), 7.79-7.77 (d, J=8.0 Hz, 1H), 7.66-7.62 (t,J=8.0 Hz, 1H), 7.51-7.49 (m, 3H), 7.45-7.41 (t, J=8.0 Hz, 1H), 7.39-7.37(d, J=7.2 Hz, 2H), 3.35-3.31 (m, 1H), 1.42-1.40 (d, J=7.2 Hz, 6H);¹³C-NMR (100 MHz, CDCl₃) δ 162.1, 152.6, 151.4, 146.7, 139.4, 138.5,129.9, 129.3, 129.2, 127.6, 127.2, 126.6, 126.3, 125.0, 114.8, 114.5,26.5, 20.5. HRMS [M+H]⁺ (ESI-TOF) calcd for C₂₂H₂₀N₄O 357.1715, found357.1719. HPLC: t_(R)=12.86 min, 99.9%.

5-chloro-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide (159)

White solid. Yield: 55%, 57 mg. ¹H-NMR (400 MHz, CDCl₃) δ 8.93 (s, 1H),8.53 (s, 1H), 8.27 (s, 1H), 8.22-8.20 (d, J=8.0 Hz, 1H), 7.86-7.84 (d,J=8.0 Hz, 1H), 7.80-7.78 (d, J=8.0 Hz, 1H), 7.68-7.64 (t, J=8.0 Hz, 1H),7.55-7.45 (m, 5H); ¹³C-NMR (100 MHz, CDCl₃) δ 159.5, 150.8, 141.6,139.9, 138.7, 138.6, 130.0, 129.6, 129.4, 129.2, 127.4, 126.5, 126.1,125.3, 119.5, 115.3, 114.6. HRMS [M+H]⁺ (ESI-TOF) calcd for C₁₉H₁₄ClN₄O349.0856, found 349.0652. HPLC: t_(R)=13.58 min, 99.0%.

5-bromo-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide (160)

White solid. Yield: 60%, 70 mg. ¹H-NMR (400 MHz, CDCl₃) δ 8.94 (s, 1H),8.56-8.54 (d, J=8.0 Hz, 1H), 8.29 (s, 1H), 8.22-8.20 (d, J=8.0 Hz, 1H),7.87-7.85 (d, J=8.4 Hz, 1H), 7.81-7.79 (d, J=8.0 Hz, 1H), 7.70-7.66 (t,J=8.0 Hz, 1H), 7.54 (m, 5H), 7.48-7.44 (d, J=8.0 Hz, 1H); ¹³C-NMR (100MHz, CDCl₃) δ 161.0, 150.8, 142.1, 138.7, 138.2, 130.0, 129.5, 129.2,127.6, 127.4, 126.5, 126.2, 125.3, 119.6, 117.9, 114.8, 114.6. HRMS[M+H]⁺ (ESI-TOF) calcd for C₁₉H₁₄BrN₄O 393.0351, found 393.0355. HPLC:t_(R)=13.12 min, 99.2%.

5-(dimethylamino)-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide(161)

White solid. Yield: 80%, 86 mg. ¹H-NMR (400 MHz, CDCl₃) δ 9.81 (s, 1H),8.59-8.57 (d, J=8.8 Hz, 1H), 8.19-8.17 (d, J=8.8 Hz, 1H), 8.15 (s, 1H),7.86-7.84 (d, J=8.0 Hz, 1H), 7.79-7.77 (d, J=8.8 Hz, 1H), 7.67-7.63 (t,J=8.0 Hz, 1H), 7.55-7.46 (m, 5H), 7.45-7.41 (t, J=8.0 Hz, 1H), 2.84 (s,6H); ¹³C-NMR (100 MHz, CDCl₃) δ 161.1, 151.4, 150.5, 146.8, 141.2,139.7, 138.3, 129.8, 129.3, 129.1, 127.5, 127.4, 126.3, 125.7, 124.8,114.7, 109.5, 43.1. HRMS [M+H]⁺ (ESI-TOF) calcd for C₂₁H₂₀N₅O 358.1668,found 358.1666. HPLC: t_(R)=12.40 min, 97.8%.

1-(2-ethylphenyl)-5-methyl-N-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide(162)

¹H-NMR (400 MHz, CDCl₃) δ 8.29 (s, 1H), 8.19 (s, 1H), 8.06 (s, 1H),7.78-7.76 (m, 3H), 7.58-7.56 (d, J=8.0 Hz, 1H), 7.46-7.38 (m, 4H),7.31-7.27 (t, J=8.0 Hz, 1H), 7.17-7.15 (d, J=8.0 Hz, 1H), 2.42 (s, 3H),2.38-2.32 (q, J=8.0 Hz, 2H), 1.10-1.06 (t, J=8.0 Hz, 3H); ¹³C-NMR (100MHz, CDCl₃) δ 162.3, 144.2, 141.8, 137.9, 136.9, 135.6, 133.9, 130.6,130.1, 129.5, 128.6, 127.7, 127.5, 126.7, 126.4, 124.9, 120.4, 117.0,114.9, 23.9, 14.4, 11.4. HRMS [M+H]⁺ (ESI-TOF) calcd for C₂₃H₂₂N₃O356.1763, found 356.1766. HPLC: t_(R)=12.83 min, 98.0%.

1-(2-ethylphenyl)-N-(isoquinolin-3-yl)-5-methyl-1H-pyrazole-4-carboxamide(163)

¹H-NMR (400 MHz, CDCl₃) δ 8.98 (s, 1H), 8.70 (s, 1H), 8.65 (s, 1H), 8.08(s, 1H), 7.88-7.7.86 (d, J=8.8 Hz, 1H), 7.83-7.81 (d, J=8.8 Hz, 1H),7.64-7.60 (t, J=8.0 Hz, 1H), 7.47-7.43 (m, 2H), 7.40-7.38 (d, J=8.0 Hz,1H), 7.33-7.29 (t, J=7.2 Hz, 1H), 7.21-7.19 (d, J=8.4 Hz, 1H), 2.47 (s,3H), 2.39-2.34 (q, J=7.2 Hz, 2H), 1.10-1.06 (t, J=7.2 Hz, 3H); ¹³C-NMR(100 MHz, CDCl₃) δ 161.9, 151.1, 146.5, 144.2, 141.8, 138.0, 136.9,130.8, 130.0, 129.5, 127.7, 126.8, 126.7, 126.4, 125.7, 114.6, 107.9,23.9, 14.4, 11.5. HRMS [M+H]⁺ (ESI-TOF) calcd for C₂₂H₂₁N₄O 357.1715,found 357.1709. HPLC: t_(R)=10.40 min, 99.9%.

1-(2-ethylphenyl)-5-methyl-N-(quinolin-3-yl)-1H-pyrazole-4-carboxamide(164)

¹H-NMR (400 MHz, CDCl₃) δ 8.88 (s, 1H), 8.78 (s, 1H), 8.69 (s, 1H), 8.13(s, 1H), 8.02-8.00 (d, J=8.8 Hz, 1H), 7.76-7.74 (d, J=8.0 Hz, 1H),7.61-7.57 (t, J=8.0 Hz, 1H), 7.52-7.48 (t, J=8.0 Hz, 1H), 7.44-7.40 (t,J=8.0 Hz, 1H), 7.38-7.36 (d, J=8.0 Hz, 1H), 7.30-7.26 (t, J=8.0 Hz, 1H),7.18-7.16 (d, J=8.0 Hz, 1H), 2.42 (s, 3H), 2.36-2.30 (d, J=8.0 Hz, 2H),1.08-1.04 (t, J=8.0 Hz, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ 162.6, 144.9,144.6, 144.5, 141.7, 138.1, 136.8, 131.9, 130.1, 129.5, 128.8, 128.2,127.7, 127.2, 126.7, 124.4, 114.4, 23.8, 14.4, 11.4. HRMS [M+H]⁺(ESI-TOF) calcd for C₂₂H₂₁N₄O 357.1715, found 357.1710. HPLC: t_(R)=7.81min, 99.4%.

1-(2-ethylphenyl)-5-methyl-N-(6-methylpyridin-2-yl)-1H-pyrazole-4-carboxamide(165)

¹H-NMR (400 MHz, CDCl₃) δ 8.52 (s, 1H), 8.12-8.10 (d, J=8.0 Hz, 1H),8.00 (s, 1H), 7.60-7.56 (t, J=8.0 Hz, 1H), 7.43-7.39 (t, J=8.0 Hz, 1H),7.37-7.35 (d, J=8.0 Hz, 1H), 7.30-7.26 (t, J=8.0 Hz, 1H), 7.17-7.15 (d,J=8.0 Hz, 1H), 6.87-6.85 (d, J=8.0 Hz, 1H), 2.42 (s, 3H), 2.39 (s, 3H),2.35-2.29 (q, J=8.0 Hz, 2H), 1.06-1.02 (t, J=8.0 Hz, 3H); ¹³C-NMR (100MHz, CDCl₃) δ 161.9, 156.7, 150.9, 144.3, 141.7, 138.6, 138.1, 136.9,130.0, 129.5, 127.7, 126.6, 119.0, 114.5, 110.9, 23.9, 23.8, 14.4, 11.4.HRMS [M+H]⁺ (ESI-TOF) calcd for C₁₉H₂₁N₄O 321.1715, found 321.1712.HPLC: t_(R)=5.18 min, 99.0%.

HPLC Conditions for foregoing compounds in Example 2. Method A: 45%Acetonitrile/55% H₂O (0.1% TFA), 1 mL/min.

Example 3: YW1149 as a Candidate Compound to Suppress Glucose Productionin Hepatocytes

The assay provided herein is a dual-luciferase assay to measureWnt/β-catenin pathway activation using a TCF/LEF responsive reporterconstruct similar to that described previously (Thorne et al., 2010). Inthis assay, HEK293 cells were transiently transfected with fireflyluciferase plasmid containing the latter construct and constitutivelyactive renilla luciferase expression plasmids as control. Lithiumchloride (LiCl), which has been previously established as an activatorof Wnt/β-catenin pathway through its direct and indirect effects onGSK3β, was used for pathway activation. The inhibition of Wnt/β-cateninpathway by a compound can be determined after its incubation with thecells for 24 hours. This assay has been validated with different Wntpathway inhibitors/activators (data not shown) and by analyzing theprotein and gene expression of pathway components via immunoblotting andRT-PCR.

As shown in FIG. 1, YW1149 is a more potent inhibitor of theWnt/β-catenin pathway (IC₅₀=74 nM) as compared to pyrvinium (IC₅₀=273nM).

In light of this evidence, a class of triazole-based inhibitors weresynthesized and tested, as described herein. This new scaffold containsfour key structural features: (1) the permanent charge, which is a majorreason for the low bioavailability of pyrvinium (Smith et al., 1976),has been removed by replacing the methylquinoline moiety with aquinolone moiety; (2) the alkenyl linker that causes the poor aqueoussolubility and poor stability of pyrvinium, was replaced by an amidelinker. The amide bond is more stable under physiological conditions;moreover, the NH and carbonyl groups can form additional H-bondinginteractions to amino acid residues critical for their inhibitoryactivities; (3) the well-documented chemically unstable2,5-dimethylpyrrole moiety (Zhu et al., 2013) has been replaced by atriazole ring; and (4) the right end phenyl group was replaced by ano-methoxy-phenyl group. These efforts have yielded the identification ofone novel pyrvinium analog YW1149, which inhibits Wnt signaling activitywith significantly improved potency (IC₅₀=74 nM) compared to pyrvinium(IC₅₀=273 nM), using the cellular luciferase gene reporter assaydescribed above. Moreover, this new inhibitor reduces glucose productionin primary hepatocytes, and is nontoxic even at higher concentrations invivo, and shows improved PK profile comparing to pyrvinium.

Example 4: Pharmacological Validation of Wnt/β-Catenin PathwayInhibition as a Strategy to Treat Type 2 Diabetes

Reduced Wnt/β-catenin signaling activity may confer a reduced risk oftype 2 diabetes. The potential of Wnt/β-catenin signaling inhibition bysmall molecules as a strategy to treat type 2 diabetes was explored.Without being limited to any one theory of the invention, the workinghypothesis is that the compounds of the invention can work throughinhibition of hepatic Wnt/β-catenin pathway to reduce glucose productionand treat type 2 diabetes.

With the transgenic mice overexpressing the Wnt pathway classicaleffector Tcf7l2, global upregulation of Wnt signaling has been suggestedto confer an increased risk of metabolic dysregulation (Bailey et al.,2015; Savic et al., 2011). In contrast, as demonstrated in Tcf7l2+/−mice, global downregulation of the pathway leads to the resistance tohigh fat diet-induced metabolic disorders (Savic et al., 2011; Yang etal., 2012). The hepatic Wnt signaling likely plays a critical role inthe effect on metabolic homeostasis. Hepatic deletion of eitherβ-catenin or Tcf7l2 reduces hepatic glucose production in adultliver-specific knockout mice which display significantly improvedmetabolic homeostasis when maintained on a high-fat diet (Boj et al.,2012; Liu et al., 2011). Thus, downregulation of Wnt/β-catenin pathwaymay serve as a strategy to treat metabolic disorders including type 2diabetes.

In the foregoing studies, intraperitoneal pyrvinium injection was ableto decrease weight gain in mice fed with a high fat diet (FIG. 2).Glucose tolerance was also improved in the mice. Pyrvinium and YW1149treatment in HepG2 cells showed results consistent with inhibition ofthe Wnt pathway—attenuation of β-catenin and the target gene c-Myc, aswell as increased Axin protein expression (FIG. 3). In addition, bothcompounds could significantly suppress glucose production and theexpression of glucose 6-phosphatase (G6P), a key gluconeogenic enzyme(Boj et al., 2012; Yang et al., 2012), and increase phosphorylation ofAMPK, a key kinase involved in energy metabolism (Shu et al., 2007), inhepatic HepG2 cells (FIG. 4). While overt toxicity was not observed by0.5 mg/kg/3 days of pyrvinium in the mice, a single dose of 2 mg/kg ofpyrvinium has caused mouse death. This narrow therapeutic window, alongwith undesirable PK properties of pyrvinium, allows the research tofocus towards YW1149 and additional analogs that are more potent Wntpathway inhibitors but possess less toxicity.

Example 5: Pharmacokinetic Properties and Toxicity of YW1149

Pyrvinium has poor bioavailability (Smith et al., 1976) and littleevidence is available for pyrvinium analogs when administered orally,which is an essential consideration in antidiabetic drug development.The objective is to characterize the absorption, distribution,metabolism and excretion (ADME) properties and toxicity of the compoundsof the invention.

Permeability studies were performed with pyrvinium and the compoundYW2013, using Madin-Darby Canine Kidney (MDCK) epithelial cell monolayerformed on transwell cell culture plates. There was significantapical-to-basolateral and basolateral-to-apical flux for YW2013 whilepyrvinium was detected below the limit of detection (data not shown).This suggested that the compounds of the invention could have improvedcellular permeability and bioavailability. The metabolic stability ofthese compounds was then estimated using YW1149 as a prototypicalcompound, with in vitro substrate depletion in mouse liver tissue S9fraction as previously described (Jones and Houston, 2004). Only minormetabolism was observed after one hour, suggesting that this compoundmight be metabolically stable (FIG. 5A). More so, YW1149 was stable inplasma for up to eight hours (FIG. 5B), which suggests thatbiotransformation, if any, would occur in the tissues.

A pilot pharmacokinetic study was followed up for both YW1149 andpyrvinium (FIG. 6). Single intravenous and oral administration ofpyrvinium pamoate (2 mg/kg) and YW1149 (10 mg/kg) was initiated in12-week old C57BL/6 mice respectively. Blood samples were collected atmultiple time points. The mouse intravenously administered withpyrvinium pamoate died after thirty minutes so blood collection wasdiscontinued. Ultra-performance liquid chromatography system with atriple quadruple detector (UPLC/TQD) was used for compound quantitation.It was found that pyrvinium exhibited little or no absorption. Theintravenous half-life of this drug was about six minutes while oralhalf-life extended to about one hour as calculated using PhoenixWinnolin non-compartmental analysis function. Intravenous YW1149 showeda half-life of one hour. The bioavailability (F) of YW1149 was 0.75,which was much higher than that of pyrvinium (0.0025).

The cytotoxicity of series of a compound of the invention was measuredusing a colorimetric assay, Cell Counting Kit-8 (Sigma) in HEK293 cells.While YW1149 was a more potent Wnt pathway inhibitor (FIG. 1), it causedless cytotoxicity with an anti-proliferation IC₅₀ above 100 μM, ascompared to pyrvinium (IC₅₀: 2 μM) (FIG. 7A). Consistently, in apreliminary survival study, mice died within 6 hours after a single doseof 2 mg/kg pyrvinium but a dose of 10 mg/kg YW1149 was tolerated well inanother group of mice (FIG. 7B).

Example 6: Cancer Cell Proliferation and Growth Inhibition Assays forCompounds of the Invention

Compounds of the invention were tested to determine their growthinhibiting activity against a variety of cancer cell lines which aredescribed in FIG. 10.

Cell Culture.

The human colorectal cancer cell lines HT-29, HCT-116, WiDr, SW620,SW480, T84; human lung cancer cell line A549; human breast cancer cellline MCF-7; human hepatocarcinoma HepG2; and human cervical cancer cellline Hela were purchased from ATCC. HT-29 and HCT116 were maintained inMcCoy's 5a with 10% FBS, HepG2 were maintained in low glucose DMEM with20% FBS and the other cells were maintained in high glucose DMEM with10% FBS.

Cell Proliferation and Growth Inhibition Assay.

HT-29, HCT-116, WiDr, SW620, SW480, T84, A549, MCF-7, HepG2, Hela cellswere cultured in respective growth medium. Cells of log phase were used.3000-5000 cells/well were seeded in 96-well plates with a 100 μL volume.After 24 h, Compounds were dissolved to 50 μM with DMSO, and a 3-foldserial dilution of the compounds from 5×10⁻⁵ M to 23×10⁻⁹ M wasperformed. 2 μL of compound solution was added to 998 μL of growthmedium, the mixture was vortexed sufficiently. 100 μL of the mixture wascorrespondingly added to the 96-well plate. 2 μL DMSO instead ofcompound solution was used as the 0% inhibitor control. Aftercoincubation for 72 h, the old medium was removed and 100 μL of 10%CCK-8 in culture medium was added. 2 h later the plates were read in themicroplate reader (Bio-Rad) at 450 nm. The data was calculated usingGraph Pad Prism version 5.0. The IC₅₀ were fitted using a nonlinearregression model with a sigmoidal dose response.

A variety of the compounds of the invention were tested as set forthherein at M (FIG. 8A) and 50 μM (FIG. 8B) for their ability to inhibitthe growth of colon cancer cells (i.e., SW480; primary carcinoma). Aspecific set of compounds displayed micro-molar IC₅₀ values as shown inFIG. 9.

As compared to pyrvinium, a number of compounds of the inventiondisplayed cytotoxic activity against A549, Hela, MCF-7, HCT116, HCT116p53, HCT116 p21−, and HepG2 cells (FIG. 11). As shown in FIG. 11,certain compounds of the invention were also nanomolar inhibitors oftranscription. Furthermore, the micromolar growth inhibitory activity ofYW1059, YW1061, YW2013, YW1128, YW2035, YW2044, and YW2049 is set forthin FIG. 12 against the WiDr, SW620, HT29, HEK_LTV, and T84 cell lines.

Specific dose response curves, comparing certain compounds of theinvention as inhibitors of β-catenin in several cell lines, are shown inFIGS. 13-16 and 18.

With a TOPflash/FOPFlash Assay against SW480 cells, the inhibitoryeffect of YW2013 against Wnt signaling, with and without LiCl wasdetermined at 100 nM (FIG. 17).

Example 7: Effect of YW2013 and YW2044 on the Expression of the GenesRegulated by Wnt Signaling in Cancer Cells

Quantitative Real-Time RT-PCR.

The total RNA extracted from the cells using TRIzol (Invitrogen) and 2μg was reverse transcribed in a 20-μl volume system (QuantiTect ReverseTranscription Kit (Qiagen)) for quantitative PCR assays. SYBR greenquantitative real-time PCR analyses were carried out using gene-specificprimers (working concentration at 250 nM) in StepOnePlus real time PCRsystem (Applied Biosystems, AB), using the housekeeping gene GAPDH as aninternal control. The PCR running procedure was as follows: 4 mindenaturing at 95° C., followed by 40 cycles of 30 seconds of denaturingat 95° C. and then annealing and extension at 60° C. for 1 min. Theprimer sequences were as follows: Axin-2 for, 5′-CTCCTTGGAGGCAAGAGC-3′(SEQ ID NO: 1); rev, 5′-GGCCACGCAGCACCGCTG-3′ (SEQ ID NO: 2); Cyclin D1for, 5′-AAGGCGGAGGAGACCTGCGCG-3′ (SEQ ID NO: 3); rev,5′-ATCGTGCGGCATTGCGGC-3′ (SEQ ID NO: 4); GAPDH for,5′-ACCACAGTCCATGCCATCAC-3′ (SEQ ID NO: 5); rev,5′-TCCACCACCCTGTTGCTGT-3′ (SEQ ID NO: 6).

YW2013 reduced mRNA expression of Wnt regulated genes (Axin-2 and/orcyclin D1) in A549 cells (FIG. 19), SW620 cells (FIGS. 20 and 21), andWiDr cells (FIG. 22). YW2044 was shown to reduce mRNA expression of Wntregulated genes in SW620 cells (FIG. 21).

Example 8: Effect of YW2013 and YW2123 on the Expression of WntSignaling Proteins

Using a Western Blot, compounds YW2013 and YW2123 were tested in SW480cells to determine their effect on the expression of Axin-2, β-catenin,and c-myc.

Western Blot:

1×10⁶ Cells of SW480 cells were seeded into 6-well plates overnight. Aconcentration of 3, 10, 30 μM/L YW2013 and 3, 10 μM/L YW2123 was addedafter 24 h, medium with 1‰ DMSO was used as the control. Cells wereexposed to treatment for 48 h. The dishes was washed twice using precoldPBS and 100 μL of RIPA then added. After incubating plates on ice for 15min, cells were scraped carefully and centrifuged for 10 minutes at14,000 g at 4° C. immediately. The remaining supernatant and lysateswere maintained at −70° C. A Bio-Rad protein assay kit (500-0002) wasused to quantitate the cell lysates. The concentration was adjusted to 2mg/ml. A ratio of 1:1 2× loading buffer was added and the samples weredenatured by boiling. Protein samples were separated on 4-15%SDS-polyacrylamide gel (SDS-PAGE) and transferred onto the PVDFmembranes (Millipore). Immune complexes were formed by incubation of theproteins with primary antibody β-catenin, c-myc, Axin-2, and GAPDH at 4°C. overnight. A second antibody with horseradish peroxidase (HRP, sigma)conjugated was used then. Blots were developed by enhancedchemiluminescence (Thermo).

As shown in FIG. 23, at least YW2013 visibly reduced the expression ofAxin-2, β-catenin, and c-myc. YW2044 also had a noticeable effect onAxin-2 expression (FIG. 23).

Example 9: Effect of Compounds of the Invention on Cancer Cell ColonyFormation

Certain compounds of the invention were tested to determine theirability to inhibit colony formation in several cancer cell lines (FIGS.24-26 and 31). Moreover, SW2013 was paired with Gefitinib to determinethe effect of a combination therapy on colony formation of SW620 cells(FIG. 31).

Colony Formation Assay.

HT-29 and SW620, SW480 cells were seeded into 6-well dishes with themedium containing 0, 1, 3, 10, 30 μM/L of YW2013 or YW2044, 500cells/well. After 2 weeks, cells were fixed with 4% paraformaldehydesolution and stained with 0.5% crystal violet for 1 h at roomtemperature. The images of colonies were captured by microscopy.

YW2044 exhibited a dose dependent reduction in colony formation in HT-29cells (FIG. 24). YW2013 exhibited a dose dependent reduction in colonyformation in SW480 cells (FIG. 25) and SW620 cells (FIG. 26).Furthermore, YW2013 exhibited a dose dependent reduction in colonyformation that was markedly increased when combined with Gefitinib,demonstrating that Gefitinib and YW2013 may provide synergistic activityagainst colony formation (FIG. 31).

Example 10: Effect of YW2013 on Cell Cycle in SW620 Cells

SW620 cells were treated with YW2013 at various concentrations (0, 1, 10μM) to determine the effect of YW2013 on the SW620 cell cycle in anunsynchronized assay (FIG. 27A) and an assay where cells were treatedwith FBS free medium for 24 hours up to synchronization before addingYW2013 (FIG. 27B).

Cell Cycle Analysis.

SW620 cells were plated in 6-well plates for 24 h, and the medium wasreplaced with medium containing 0, 1, 10, μM/L of YW2013. Afterincubation for 24 h, the cells were harvested by trypsinization and thenfixed with 70% 4° C. ethanol. Intracellular DNA was stained with 50ng/ml propidium iodide in the dark for 30 min at room temperature, andthe percentages of different phase of cells were determined by flowcytometry (BD FACScan; BD Biosciences).

The results shown FIGS. 28 and 29 indicate cell cycle arrest in the Giand S phases for both unsynchronized (FIG. 28) and synchronized (FIG.29) assays.

Example 11: YW2013 Induced Apoptosis in SW620 Cells

Annexin-V/AAD-7 Double-Staining Assay.

SW620 cells were treated with 0, 3, 10, 30 μM/L of YW2013 for 48 h. Thenthey were harvested and washed with PBS. Apoptotic cells were determinedwith an FITC Annexin V Apoptosis Detection Kit according to themanufacturer's protocol. Briefly, the cells were washed and subsequentlyincubated for 15 min at room temperature in the dark in 100 μL of 1×binding buffer containing 2 μL of Annexin V-FITC and 2 μL of AAD-7.After 30 min, apoptosis was analyzed by BD FACSCanto II Flow Cytometer.

As shown in FIG. 30, YW2013 induced apoptosis in SW620 cells in a dosedependent manner.

Furthermore, the effect of YW2013 in combination of Gefitinib is shownin FIG. 32 where the two compounds were tested as a combination therapyfor SW620 cells. Gefitinib was tested at 1, 10, and 30 μM.

Example 12: Characterization of Wnt/β-Catenin Signaling Inhibitors(e.g., YW1128) Against Non-Alcoholic Fatty Liver Disease and itsSequelae

Wnt/β-catenin signalling downregulation appears to fully reversenon-alcoholic fatty liver disease in a mouse model. The Wnt/β-cateninsignaling inhibitors disclosed herein may be used in the treatment ofnon-alcoholic fatty liver disease (NAFLD) and its sequelae non-alcoholicsteatohepatitis (NASH). These inhibitors are expected to safely inhibitthe Wnt/β-catenin pathway with improved potency, metabolic stability,and bioavailability.

The Wnt/β-catenin signaling pathway has been long recognized to play apivotal role in cell proliferation, differentiation, and organdevelopment. As an emerging research area, however, the link betweenWnt/β-catenin pathway and metabolic diseases has only been appreciatedrecently. For example, a strong association exists between type 2diabetes risk and single nucleotide polymorphisms (SNPs) in TCF7L2, aclassic effector of Wnt/β-catenin pathway. Similar genetic evidenceexists for additional modulators of Wnt signaling pathway such as WNT5B,WNT1B, and LRP6. Follow-up genetic studies have indicated that globaldownregulation of Wnt/β-catenin signaling activity leads to overallimproved metabolic homeostasis in diabetic animal models

The metabolic disease NAFLD is the most common form of chronic liverdisease and ranges in severity from relatively simple benign steatosisto NASH, which is highly prevalent in type 2 diabetes or obese patients,and is a burgeoning public health problem due to the global diabetes andobesity epidemic. Dietary control and exercise are currently therecommendation to reverse NAFLD/NASH; however, their long-termeffectiveness is uncertain because many patients are unable to comply.Thus, an effective pharmacological therapeutic is highly in demand.

Reducing β-catenin expression by antisense oligonucleotides decreasesexpression of enzymes involved in hepatic fatty acid esterification andameliorates diet-induced hepatic steatosis and insulin resistance.Indeed, an antisense oligonucleotide against β-catenin could totallyreverse diet-induced fatty liver and obesity back to normal, improveglucose tolerance, and reduce fasting glucose levels in the blood ofmice.

These results support targeting the Wnt/β-catenin pathway as a strategyto treat NAFLD.

Mice were treated with YW1128 and representative liver histology wasobserved through H&E staining. C57BL/6 mice were placed on a high-fatdiet. Seven weeks later (week 0), the mice received either vehicle orYW1128 by IP injection for 11 weeks. Regarding treatment with YW1128,the mice were initially treated at a dose of 10 mg/kg/2 days, which wasincreased to 40 mg/kg/2 days from week 8. The mice were then euthanizedat the end of 11 weeks. Liver histology for vehicle (FIGS. 33A and 33B)and YW1128 (FIGS. 33C and 33D) was examined by H&E staining.

An intraperitoneal glucose tolerance test (IPGTT) was conducted onhigh-fat diet (HFD) groups at the end of the study. C57BL/6 mice (n=3-4per group) were put on a high fat diet. Seven weeks later (week 0), themice received either vehicle or YW1128 by IP injection for 11 weeks.Regarding the treatment with YW1128, the mice were initially treated ata dose of 10 mg/kg/2 days, which was increased to 40 mg/kg/2 days fromweek 8. The results of this study are set forth in FIGS. 34A and 34B.FIG. 34A describes the glucose levels at up to 120 minutespost-injection at week 0. FIG. 34B describes the glucose levels at up to120 minutes post-injection at week 11, where *P<0.05 and **P<0.01,compared to the YW1128 group.

The effect of YW1128 on body weight was also observed in mice havingnormal diets (NC) and those having high-fat (HF) diets. C57BL/6 mice(n=3-4 per group) were put on either an HF diet or an NC diet. Sevenweeks later, the mice received either YW1128 or vehicle by IP injection.Regarding the treatment with YW1128, the mice were treated at a dose of40 mg/kg/2 days for seven weeks. The results of such study are shown inFIG. 35, where *P<0.05 for the comparison between HF-vehicle and theother three groups.

Given the importance of Wnt/β-catenin signaling in regulation of cellproliferation and differentiation, there are questions regardinglong-term inhibition of canonical Wnt signaling in chronic diseases thatmay result in toxicity, in particular in tissues with high cellularturnover. It has been observed that injection of YW1128 couldsignificantly improve glucose tolerance and decrease body weight gain inthe mice fed on high-fat diet (FIGS. 33A to 33D, 34A and 34B, and 35).Furthermore, the mice that received YW1128 did not exhibit any histologyof fatty liver disease which was apparent in those received vehicle. Inaddition, the subchronic treatment of YW1128 did not cause any obvioustoxicity in the mice.

Example 13: Effect of YW1128 on a High-Fat Diet (HFD)-Induced Steatosis

C57BL/6 mice (n=7/group) were put on a Western high-fat diet (HFD) ornormal chow diet (NCD). Seven weeks later, the mice received eithervehicle or YW1128 by I.P., 40 mg/kg/2 days, for 11 weeks. Representativeliver histology was measured by H&E staining (FIG. 36A). Anintraperitoneal glucose tolerance test (IPGTT) was conducted at the endof the study (FIG. 36B). Body weight for the mice was monitored duringthe treatment (FIG. 36C). Increased phosphorylation of AMPKα1 atthreonine 172 (T172) (p-AMPKα) in YW1128-treated livers was observed ascompared to vehicle-treated livers (FIG. 36D). CK1a did not show anysignificant change.

Example 14: YW2065 Inhibited SW620 Xenograft Tumor Growth in Nude Mice

Six-week old nude mice were injected with 2×106 SW620 cellssubcutaneously. 10 days after inoculation, mice received an i.p.injection of YW2065 at 10 mg/kg or 50 mg/kg or vehicle each day. Thetumor growth (FIG. 37A) was measured every other day. The mice wereeuthanized at day 32, and tumors were weighed (FIG. 37B). Body weightchange was monitored during the study (FIG. 37C). As shown during thestudy compared to vehicle, YW2065 markedly inhibited tumor growth over a32 day study.

Example 15: Effects of YW2065 Treatment on Mitochondrial Function andMorphology in Colon Cancer Cells

Mitochondrial function and morphology was determined in SW480 cellstreated with YW2065. YW2065 produced a reduced oxygen consumption rate(OCR) (FIG. 38A) and inhibited ATP production as a function of dosage(FIG. 38B). YW2065 (10 μM) caused short and punctuated mitochondria inSW480 cells after 4 hours of treatment (FIG. 38C). Furthermore, YW2065increased ROS generation in SW480 cells as evaluated by staining thetreated cells with DHE.

A number of patent and non-patent publications are cited herein in orderto describe the state of the art to which this invention pertains. Theentire disclosure of each of these publications is incorporated byreference herein.

While certain embodiments of the present invention have been describedand/or exemplified above, various other embodiments will be apparent tothose skilled in the art from the foregoing disclosure. The presentinvention is, therefore, not limited to the particular embodimentsdescribed and/or exemplified, but is capable of considerable variationand modification without departure from the scope and spirit of theappended claims.

Moreover, as used herein, the term “about” means that dimensions, sizes,formulations, parameters, shapes and other quantities andcharacteristics are not and need not be exact, but may be approximateand/or larger or smaller, as desired, reflecting tolerances, conversionfactors, rounding off, measurement error and the like, and other factorsknown to those of skill in the art. In general, a dimension, size,formulation, parameter, shape or other quantity or characteristic is“about” or “approximate” whether or not expressly stated to be such. Itis noted that embodiments of very different sizes, shapes and dimensionsmay employ the described arrangements.

Furthermore, the transitional terms “comprising”, “consistingessentially of” and “consisting of”, when used in the appended claims,in original and amended form, define the claim scope with respect towhat unrecited additional claim elements or steps, if any, are excludedfrom the scope of the claim(s). The term “comprising” is intended to beinclusive or open-ended and does not exclude any additional, unrecitedelement, method, step or material. The term “consisting of” excludes anyelement, step or material other than those specified in the claim and,in the latter instance, impurities ordinary associated with thespecified material(s). The term “consisting essentially of” limits thescope of a claim to the specified elements, steps or material(s) andthose that do not materially affect the basic and novelcharacteristic(s) of the claimed invention. All compounds, compositions,formulations, and methods described herein that embody the presentinvention can, in alternate embodiments, be more specifically defined byany of the transitional terms “comprising,” “consisting essentially of,”and “consisting of.”

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What is claimed is:
 1. A method of treating or preventing a diseasealleviated by inhibiting Wnt/β-catenin signaling in a patient in need ofsaid treatment or prevention, the method comprising administering atherapeutically effective amount of one or more compounds having theformula:

wherein R₁ and R₂ each can independently represent a substituentselected from the group consisting of H and substituted or unsubstitutedalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl,alkoxy, carboxy, carbalkoxy, and carboxamido; R₃ represents asubstituent selected from the group consisting of substituted orunsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle,and heteroaryl; n represents an integer of 0 to 2, Z represents one ormore substituted or unsubstituted alkyl substituents when n is 1 or 2;X₁ represents N or CR₄; X₂ represents N or CR₅; X₃ represents N or CR₆;R₄, R₅, and R₆ each can independently represent a substituent selectedfrom the group consisting of H, OH, NO₂, CN, halo, and substituted orunsubstituted alkyl, alkylcarbonyl, alkenyl, alkynyl, cycloalkyl, aryl,heterocycle, heteroaryl, amino, alkoxy, carboxy, carbalkoxy,carboxamido, sulfonyl, sulfonamido, sulfinyl, monoalkylaminosulfinyl,dialkylaminosulfinyl, monoalkylaminosulfonyl, dialkylaminosulfonyl,alkylsulfonylamino, hydroxysulfonyloxy, alkoxysulfonyloxy,alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, alkylsulfonylalkyl,monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl,monoalkylaminosulfinylalkyl, and dialkylaminosulfinylalkyl; wherein whenboth are present, R₄ and R₅ can be taken together to form a substitutedor unsubstituted m-membered cycloalkyl or heterocycle, wherein mrepresents an integer of 5 to 7; or the pharmaceutically acceptablesalts of said one or more compounds; with the proviso that: when X₁ andX₂ represent CR₄ and CR₅, respectively, then R₃ is substituted aryl; andcompounds wherein R₁ and R₂ each are H and substituted aryl, R₃ issubstituted aryl, n is 0, X₁ is N, X₂ is N, X₃ is CR₆, and R₆ is alkyl,are excluded.
 2. The method of claim 1, wherein the one or morecompounds are selected from the group consisting of:2,5-Dimethyl-N-(pyridin-2-yl)-1-(p-tolyl)-1H-pyrrole-3-carboxamide,2,5-Dimethyl-N-(pyrazin-2-yl)-1-(p-tolyl)-1H-pyrrole-3-carboxamide,2,5-Dimethyl-N-(4-phenylthiazol-2-yl)-1-(p-tolyl)-1H-pyrrole-3-carboxamide,N-Benzyl-2,5-dimethyl-1-(p-tolyl)-1H-pyrrole-3-carboxamide,5-Methyl-N-(pyridin-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(6-methylpyridin-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(pyridin-2-ylmethyl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(2-methyl-4-oxo-4H-chromen-7-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(3-methylisoxazol-5-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,N-(4,5-diphenylthiazol-2-yl)-5-methyl-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(1-methyl-1H-benzo[d]imidazol-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(quinolin-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(naphthalen-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,N-(benzo[d]thiazol-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(4-phenylthiazol-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,1-(2,3-Dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2,4-Dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(3-Chlorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Bromophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Cyanophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Methoxyphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(4-Fluoro-2-nitrophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Acetylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Carbamoylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-([1,1′-biphenyl]-2-yl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-1-(2-morpholinophenyl)-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-1-(naphthalen-1-yl)-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-fluorophenyl)-5-isopropyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,5-Ethyl-1-(2-fluorophenyl)-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-pyrazole-4-carboxamide,1-(2-Fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-Bromophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,2,5-Dimethyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-imidazole-4-carboxamide,1-(2-Fluorophenyl)-2,5-dimethyl-N-(quinolin-2-yl)-1H-imidazole-4-carboxamide,1-(2-Bromophenyl)-2,5-dimethyl-N-(quinolin-2-yl)-1H-imidazole-4-carboxamide,2,5-Dimethyl-1-phenyl-N-(quinolin-2-yl)-1H-imidazole-4-carboxamide,1-(2-Chlorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide1-(2-Ethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,6-dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(Tert-butyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,5-dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,4-difluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-methyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-cyclohexyl-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-methyl-1-(1-phenylethyl)-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-methyl-N-(quinolin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide,5-methyl-1-(3-methylpyridin-2-yl)-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(3-chloro-2-fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,6-difluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-bromo-6-fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-methyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-3-carboxamide,5-methyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-pyrazole-3-carboxamide,1-(2-ethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-3-carboxamide,1-phenyl-N-(quinolin-2-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxamide,1-phenyl-N-(quinolin-2-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide,3,5-dimethyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,5-dimethylphenyl)-3,5-dimethyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-bromophenyl)-3,5-dimethyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-ethyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-isopropyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-chloro-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-bromo-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-(dimethylamino)-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-ethylphenyl)-5-methyl-N-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide,1-(2-ethylphenyl)-N-(isoquinolin-3-yl)-5-methyl-1H-pyrazole-4-carboxamide,1-(2-ethylphenyl)-5-methyl-N-(quinolin-3-yl)-1H-pyrazole-4-carboxamide,1-(2-ethylphenyl)-5-methyl-N-(6-methylpyridin-2-yl)-1H-pyrazole-4-carboxamide,N-(6-bromoquinolin-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-(morpholinomethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-((4-methylpiperazin-1-yl)methyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-(pyrrolidin-1-ylmethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,N-(6-((diethylamino)methyl)quinolin-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-(piperidin-1-ylmethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,tert-butyl4-((2-(5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamido)quinolin-6-yl)methyl)piperazine-1-carboxylate,N-(6-((dimethylamino)methyl)quinolin-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-(thiomorpholinomethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-((4-morpholinopiperidin-1-yl)methyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,and5-methyl-N-(6-((4-(4-methylpiperazin-1-yl)piperidin-1-yl)methyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,and the pharmaceutically acceptable salts thereof.
 3. The method ofclaim 1, wherein the one or more compounds are of the formula:

wherein R₇ represents a substituent selected from the group consistingof H and substituted or unsubstituted alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heterocycle, heteroaryl, alkoxy, carboxy, carbalkoxy,and carboxamido; R₈ represents a substituent selected from the groupconsisting of H, OH, NO₂, CN, halo, and substituted or unsubstitutedalkyl, alkenyl, alkynyl, aryl, amino, and alkoxy; R₉, R₁₀, R₁₁, R₁₂, andR₁₃ each can independently represent a substituent selected from thegroup consisting of H, OH, NO₂, CN, halo, and substituted orunsubstituted alkyl, alkylcarbonyl, alkenyl, alkynyl, cycloalkyl, aryl,heterocycle, heteroaryl, amino, alkoxy, carboxy, carbalkoxy,carboxamido, sulfonyl, sulfonamido, sulfinyl, monoalkylaminosulfinyl,dialkylaminosulfinyl, monoalkylaminosulfonyl, dialkylaminosulfonyl,alkylsulfonylamino, hydroxysulfonyloxy, alkoxysulfonyloxy,alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, alkylsulfonylalkyl,monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl,monoalkylaminosulfinylalkyl, and dialkylaminosulfinylalkyl, with theproviso R₁₁ is not H when R₉, R₁₀, R₁₂, and R₁₃ each is independently H;X₄ represents N or CR₁₄; X₅ represents N or CR₁₅; R₁₄ and R₁₅ each canindependently represent a substituent selected from the group consistingof H, OH, NO₂, CN, halo, and substituted or unsubstituted alkyl,alkylcarbonyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle,heteroaryl, amino, alkoxy, carboxy, carbalkoxy, carboxamido, sulfonyl,sulfonamido, sulfinyl, monoalkylaminosulfinyl, dialkylaminosulfinyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino,hydroxysulfonyloxy, alkoxysulfonyloxy, alkylsulfonyloxy,hydroxysulfonyl, alkoxysulfonyl, alkylsulfonylalkyl,monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl,monoalkylaminosulfinylalkyl, and dialkylaminosulfinylalkyl; wherein ifX₄ and X₅ are CR₁₄ and CR₁₅, respectively, then R₁₄ and R₁₅ can be takentogether to form a substituted or unsubstituted m-membered cycloalkyl orheterocycle, wherein m is an integer of 5 to 7; or the pharmaceuticallyacceptable salts of said one or more compounds; with the proviso that:when X₄ and X₅ are CR₁₄ and CR₁₅ respectively, then at least one of R₉,R₁₀, R₁₁, R₁₂, and R₁₃ is not H; when X₄ is N and X₅ is N, then R₇ isnot substituted aryl; and compounds wherein R₇ is substitutedheteroaryl; R₈ is alkyl; R₉, R₁₀, R₁₂, and R₁₃ are each H; R₁₁ is halo;X₄ is N; and X₅ is N are excluded.
 4. The method of claim 3, wherein theone or more compounds are selected from the group consisting of:2,5-Dimethyl-N-(pyridin-2-yl)-1-(p-tolyl)-1H-pyrrole-3-carboxamide,2,5-Dimethyl-N-(pyrazin-2-yl)-1-(p-tolyl)-1H-pyrrole-3-carboxamide,2,5-Dimethyl-N-(4-phenylthiazol-2-yl)-1-(p-tolyl)-1H-pyrrole-3-carboxamide,N-Benzyl-2,5-dimethyl-1-(p-tolyl)-1H-pyrrole-3-carboxamide,5-Methyl-N-(pyridin-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(6-methylpyridin-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(pyridin-2-ylmethyl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(2-methyl-4-oxo-4H-chromen-7-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(3-methylisoxazol-5-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,N-(4,5-diphenylthiazol-2-yl)-5-methyl-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(1-methyl-1H-benzo[d]imidazol-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(quinolin-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(naphthalen-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,N-(benzo[d]thiazol-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(4-phenylthiazol-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,1-(2,3-Dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2,4-Dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(3-Chlorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Bromophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Cyanophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Methoxyphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(4-Fluoro-2-nitrophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Acetylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Carbamoylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-([1,1′-biphenyl]-2-yl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-1-(2-morpholinophenyl)-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-1-(naphthalen-1-yl)-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-fluorophenyl)-5-isopropyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,5-Ethyl-1-(2-fluorophenyl)-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-pyrazole-4-carboxamide,1-(2-Fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-Bromophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,2,5-Dimethyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-imidazole-4-carboxamide,1-(2-Fluorophenyl)-2,5-dimethyl-N-(quinolin-2-yl)-1H-imidazole-4-carboxamide,1-(2-Bromophenyl)-2,5-dimethyl-N-(quinolin-2-yl)-1H-imidazole-4-carboxamide,2,5-Dimethyl-1-phenyl-N-(quinolin-2-yl)-1H-imidazole-4-carboxamide,1-(2-Chlorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-Ethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,6-dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,5-dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,4-difluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-methyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-methyl-1-(3-methylpyridin-2-yl)-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(3-chloro-2-fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,6-difluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-bromo-6-fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,3,5-dimethyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,5-dimethylphenyl)-3,5-dimethyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-bromophenyl)-3,5-dimethyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-ethyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-isopropyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-chloro-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-bromo-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-(dimethylamino)-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-ethylphenyl)-5-methyl-N-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide,1-(2-ethylphenyl)-N-(isoquinolin-3-yl)-5-methyl-1H-pyrazole-4-carboxamide,1-(2-ethylphenyl)-5-methyl-N-(quinolin-3-yl)-1H-pyrazole-4-carboxamide,1-(2-ethylphenyl)-5-methyl-N-(6-methylpyridin-2-yl)-1H-pyrazole-4-carboxamide,N-(6-bromoquinolin-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-(morpholinomethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-((4-methylpiperazin-1-yl)methyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-(pyrrolidin-1-ylmethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,N-(6-((diethylamino)methyl)quinolin-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-(piperidin-1-ylmethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,tert-butyl4-((2-(5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamido)quinolin-6-yl)methyl)piperazine-1-carboxylate,N-(6-((dimethylamino)methyl)quinolin-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-(thiomorpholinomethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-((4-morpholinopiperidin-1-yl)methyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,and5-methyl-N-(6-((4-(4-methylpiperazin-1-yl)piperidin-1-yl)methyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,and the pharmaceutically acceptable salts thereof.
 5. The method ofclaim 1, wherein the one or more compounds are selected from the groupconsisting ofN-(benzo[d]thiazol-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,2,5-Dimethyl-N-(4-phenylthiazol-2-yl)-1-(p-tolyl)-1H-pyrrole-3-carboxamide,5-Methyl-N-(naphthalen-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(6-methylpyridin-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Bromophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Methoxyphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(3-Chlorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2,3-Dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Cyanophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Acetylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2,4-Dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-pyrazole-4-carboxamide,5-Ethyl-1-(2-fluorophenyl)-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-fluorophenyl)-5-isopropyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,N-(benzo[d]thiazol-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-Chlorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-Ethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(Tert-butyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide, and5-methyl-1-(1-phenylethyl)-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,and the pharmaceutically acceptable salts thereof.
 6. The method ofclaim 3, wherein the one or more compounds comprise1-(2-Methoxyphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-pyrazole-4-carboxamide,1-(2-Ethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-Bromophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,or a pharmaceutically acceptable salt thereof.
 7. The method of claim 1,wherein the disease is cancer or a metabolic disease.
 8. The method ofclaim 1, wherein the disease is selected from the group consisting oftype 2 diabetes, obesity, hyperlipidemia, fatty liver disease,adrenocortical cancer, hepatocellular cancer, hepatoblastoma, malignantmelanoma, ovarian cancer, Wilm's tumor, Barrett's esophageal cancer,prostate cancer, pancreatic cancer, bladder cancer, breast cancer,gastric cancer, head & neck cancer, lung cancer, mesothelioma, cervicalcancer, uterine cancer, myeloid leukemia cancer, lymphoid leukemiacancer, pilometricoma cancer, medulloblastoma cancer, glioblastoma, andfamilial adenomatous polyposis.
 9. The method of claim 1, wherein thedisease is type 2 diabetes.
 10. The method of claim 1, wherein thedisease is colon cancer.
 11. A compound of the formula:

wherein R₁ and R₂ each can independently represent a substituentselected from the group consisting of H and substituted or unsubstitutedalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl,alkoxy, carboxy, carbalkoxy, and carboxamido; R₃ represents asubstituent selected from the group consisting of substituted orunsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle,and heteroaryl; n represents an integer of 0 to 2, Z represents one ormore substituted or unsubstituted alkyl substituents when n is 1 or 2;X₁ represents N or CR₄; X₂ represents N or CR₅; X₃ represents N or CR₆;R₄, R₅, and R₆ each can independently represent a substituent selectedfrom the group consisting of H, OH, NO₂, CN, halo, and substituted orunsubstituted alkyl, alkylcarbonyl, alkenyl, alkynyl, cycloalkyl, aryl,heterocycle, heteroaryl, amino, alkoxy, carboxy, carbalkoxy,carboxamido, sulfonyl, sulfonamido, sulfinyl, monoalkylaminosulfinyl,dialkylaminosulfinyl, monoalkylaminosulfonyl, dialkylaminosulfonyl,alkylsulfonylamino, hydroxysulfonyloxy, alkoxysulfonyloxy,alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, alkylsulfonylalkyl,monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl,monoalkylaminosulfinylalkyl, and dialkylaminosulfinylalkyl; wherein whenboth are present, R₄ and R₅ can be taken together to form a substitutedor unsubstituted m-membered cycloalkyl or heterocycle, wherein mrepresents an integer of 5 to 7; or the pharmaceutically acceptablesalts of said one or more compounds; with the proviso that: when X₁ andX₂ represent CR₄ and CR₅, respectively, then R₃ is substituted aryl; andcompounds wherein R₁ and R₂ each are H and substituted aryl, R₃ issubstituted aryl, n is 0, X₁ is N, X₂ is N, X₃ is CR₆, and R₆ is alkyl,are excluded.
 12. The compound of claim 11, wherein the compound isselected from the group consisting of:2,5-Dimethyl-N-(pyridin-2-yl)-1-(p-tolyl)-1H-pyrrole-3-carboxamide,2,5-Dimethyl-N-(pyrazin-2-yl)-1-(p-tolyl)-1H-pyrrole-3-carboxamide,2,5-Dimethyl-N-(4-phenylthiazol-2-yl)-1-(p-tolyl)-1H-pyrrole-3-carboxamide,N-Benzyl-2,5-dimethyl-1-(p-tolyl)-1H-pyrrole-3-carboxamide,5-Methyl-N-(pyridin-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(6-methylpyridin-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(pyridin-2-ylmethyl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(2-methyl-4-oxo-4H-chromen-7-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(3-methylisoxazol-5-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,N-(4,5-diphenylthiazol-2-yl)-5-methyl-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(1-methyl-1H-benzo[d]imidazol-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(quinolin-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(naphthalen-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,N-(benzo[d]thiazol-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(4-phenylthiazol-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,1-(2,3-Dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2,4-Dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(3-Chlorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Bromophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Cyanophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Methoxyphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(4-Fluoro-2-nitrophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Acetylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Carbamoylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-([1,1′-biphenyl]-2-yl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-1-(2-morpholinophenyl)-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-1-(naphthalen-1-yl)-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-fluorophenyl)-5-isopropyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,5-Ethyl-1-(2-fluorophenyl)-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-pyrazole-4-carboxamide,1-(2-Fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-Bromophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,2,5-Dimethyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-imidazole-4-carboxamide,1-(2-Fluorophenyl)-2,5-dimethyl-N-(quinolin-2-yl)-1H-imidazole-4-carboxamide,1-(2-Bromophenyl)-2,5-dimethyl-N-(quinolin-2-yl)-1H-imidazole-4-carboxamide,2,5-Dimethyl-1-phenyl-N-(quinolin-2-yl)-1H-imidazole-4-carboxamide,1-(2-Chlorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide1-(2-Ethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,6-dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(Tert-butyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,5-dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,4-difluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-methyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-cyclohexyl-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-methyl-1-(1-phenylethyl)-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-methyl-N-(quinolin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide,5-methyl-1-(3-methylpyridin-2-yl)-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(3-chloro-2-fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,6-difluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-bromo-6-fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-methyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-3-carboxamide,5-methyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-pyrazole-3-carboxamide,1-(2-ethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-3-carboxamide,1-phenyl-N-(quinolin-2-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxamide,1-phenyl-N-(quinolin-2-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide,3,5-dimethyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,5-dimethylphenyl)-3,5-dimethyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-bromophenyl)-3,5-dimethyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-ethyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-isopropyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-chloro-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-bromo-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-(dimethylamino)-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-ethylphenyl)-5-methyl-N-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide,1-(2-ethylphenyl)-N-(isoquinolin-3-yl)-5-methyl-1H-pyrazole-4-carboxamide,1-(2-ethylphenyl)-5-methyl-N-(quinolin-3-yl)-1H-pyrazole-4-carboxamide,1-(2-ethylphenyl)-5-methyl-N-(6-methylpyridin-2-yl)-1H-pyrazole-4-carboxamide,N-(6-bromoquinolin-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-(morpholinomethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-((4-methylpiperazin-1-yl)methyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-(pyrrolidin-1-ylmethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,N-(6-((diethylamino)methyl)quinolin-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-(piperidin-1-ylmethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,tert-butyl4-((2-(5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamido)quinolin-6-yl)methyl)piperazine-1-carboxylate,N-(6-((dimethylamino)methyl)quinolin-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-(thiomorpholinomethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-((4-morpholinopiperidin-1-yl)methyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,and5-methyl-N-(6-((4-(4-methylpiperazin-1-yl)piperidin-1-yl)methyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,and the pharmaceutically acceptable salts of said compound.
 13. Thecompound of claim 11, comprising the formula:

wherein R₇ represents a substituent selected from the group consistingof H and substituted or unsubstituted alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heterocycle, heteroaryl, alkoxy, carboxy, carbalkoxy,and carboxamido; R₈ represents a substituent selected from the groupconsisting of H, OH, NO₂, CN, halo, and substituted or unsubstitutedalkyl, alkenyl, alkynyl, aryl, amino, and alkoxy; R₉, R₁₀, R₁₁, R₁₂, andR₁₃ each can independently represent a substituent selected from thegroup consisting of H, OH, NO₂, CN, halo, and substituted orunsubstituted alkyl, alkylcarbonyl, alkenyl, alkynyl, cycloalkyl, aryl,heterocycle, heteroaryl, amino, alkoxy, carboxy, carbalkoxy,carboxamido, sulfonyl, sulfonamido, sulfinyl, monoalkylaminosulfinyl,dialkylaminosulfinyl, monoalkylaminosulfonyl, dialkylaminosulfonyl,alkylsulfonylamino, hydroxysulfonyloxy, alkoxysulfonyloxy,alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, alkylsulfonylalkyl,monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl,monoalkylaminosulfinylalkyl, and dialkylaminosulfinylalkyl, with theproviso R₁₁ is not H when R₉, R₁₀, R₁₂, and R₁₃ each is independently H;X₄ represents N or CR₁₄; X₅ represents N or CR₁₅; R₁₄ and R₁₅ each canindependently represent a substituent selected from the group consistingof H, OH, NO₂, CN, halo, and substituted or unsubstituted alkyl,alkylcarbonyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle,heteroaryl, amino, alkoxy, carboxy, carbalkoxy, carboxamido, sulfonyl,sulfonamido, sulfinyl, monoalkylaminosulfinyl, dialkylaminosulfinyl,monoalkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino,hydroxysulfonyloxy, alkoxysulfonyloxy, alkylsulfonyloxy,hydroxysulfonyl, alkoxysulfonyl, alkylsulfonylalkyl,monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl,monoalkylaminosulfinylalkyl, and dialkylaminosulfinylalkyl; wherein ifX₄ and X₅ are CR₁₄ and CR₁₅, respectively, then R₁₄ and R₁₅ can be takentogether to form a substituted or unsubstituted m-membered cycloalkyl orheterocycle, wherein m is an integer of 5 to 7; or the pharmaceuticallyacceptable salts of said one or more compounds; with the proviso that:when X₄ and X₅ are CR₁₄ and CR₁₅, respectively, then at least one of R₉,R₁₀, R₁₁, R₁₂, and R₁₃ is not H; when X₄ is N and X₅ is N, then R₇ isnot substituted aryl; and compounds wherein R₇ is substitutedheteroaryl; R₈ is alkyl; R₉, R₁₀, R₁₂, and R₁₃ are each H; R₁₁ is halo;X₄ is N; and X₅ is N are excluded.
 14. The compound of claim 13, whereinthe compound is selected from the group consisting of:2,5-Dimethyl-N-(pyridin-2-yl)-1-(p-tolyl)-1H-pyrrole-3-carboxamide,2,5-Dimethyl-N-(pyrazin-2-yl)-1-(p-tolyl)-1H-pyrrole-3-carboxamide,2,5-Dimethyl-N-(4-phenylthiazol-2-yl)-1-(p-tolyl)-1H-pyrrole-3-carboxamide,N-Benzyl-2,5-dimethyl-1-(p-tolyl)-1H-pyrrole-3-carboxamide,5-Methyl-N-(pyridin-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(6-methylpyridin-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(pyridin-2-ylmethyl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(2-methyl-4-oxo-4H-chromen-7-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(3-methylisoxazol-5-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,N-(4,5-diphenylthiazol-2-yl)-5-methyl-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(1-methyl-1H-benzo[d]imidazol-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(quinolin-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(naphthalen-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,N-(benzo[d]thiazol-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(4-phenylthiazol-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,1-(2,3-Dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2,4-Dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(3-Chlorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Bromophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Cyanophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Methoxyphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(4-Fluoro-2-nitrophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Acetylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Carbamoylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-([1,1′-biphenyl]-2-yl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-1-(2-morpholinophenyl)-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-1-(naphthalen-1-yl)-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-fluorophenyl)-5-isopropyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,5-Ethyl-1-(2-fluorophenyl)-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-pyrazole-4-carboxamide,1-(2-Fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-Bromophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,2,5-Dimethyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-imidazole-4-carboxamide,1-(2-Fluorophenyl)-2,5-dimethyl-N-(quinolin-2-yl)-1H-imidazole-4-carboxamide,1-(2-Bromophenyl)-2,5-dimethyl-N-(quinolin-2-yl)-1H-imidazole-4-carboxamide,2,5-Dimethyl-1-phenyl-N-(quinolin-2-yl)-1H-imidazole-4-carboxamide,1-(2-Chlorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-Ethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,6-dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,5-dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,4-difluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-methyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-methyl-1-(3-methylpyridin-2-yl)-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(3-chloro-2-fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,6-difluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-bromo-6-fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,3,5-dimethyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,5-dimethylphenyl)-3,5-dimethyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-bromophenyl)-3,5-dimethyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-ethyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-isopropyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-chloro-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-bromo-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-(dimethylamino)-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-ethylphenyl)-5-methyl-N-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide,1-(2-ethylphenyl)-N-(isoquinolin-3-yl)-5-methyl-1H-pyrazole-4-carboxamide,1-(2-ethylphenyl)-5-methyl-N-(quinolin-3-yl)-1H-pyrazole-4-carboxamide,1-(2-ethylphenyl)-5-methyl-N-(6-methylpyridin-2-yl)-1H-pyrazole-4-carboxamide,N-(6-bromoquinolin-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-(morpholinomethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-((4-methylpiperazin-1-yl)methyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-(pyrrolidin-1-ylmethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,N-(6-((diethylamino)methyl)quinolin-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-(piperidin-1-ylmethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,tert-butyl4-((2-(5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamido)quinolin-6-yl)methyl)piperazine-1-carboxylate,N-(6-((dimethylamino)methyl)quinolin-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-(thiomorpholinomethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-((4-morpholinopiperidin-1-yl)methyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,and5-methyl-N-(6-((4-(4-methylpiperazin-1-yl)piperidin-1-yl)methyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,and the pharmaceutically acceptable salts of said compound.
 15. Thecompound of claim 11, wherein the compound is selected from the groupconsisting ofN-(benzo[d]thiazol-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,2,5-Dimethyl-N-(4-phenylthiazol-2-yl)-1-(p-tolyl)-1H-pyrrole-3-carboxamide,5-Methyl-N-(naphthalen-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(6-methylpyridin-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Bromophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Methoxyphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(3-Chlorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2,3-Dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Cyanophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Acetylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2,4-Dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-pyrazole-4-carboxamide,5-Ethyl-1-(2-fluorophenyl)-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-fluorophenyl)-5-isopropyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,N-(benzo[d]thiazol-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-Chlorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-Ethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(Tert-butyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide, and5-methyl-1-(1-phenylethyl)-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,and the pharmaceutically acceptable salts of said compound.
 16. Thecompound of claim 13, wherein the compound is selected from the groupconsisting of1-(2-Methoxyphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-pyrazole-4-carboxamide,1-(2-Bromophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,and1-(2-Ethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,and the pharmaceutically acceptable salts of said compound.
 17. Thecompound of claim 13, wherein the compound is1-(2-Methoxyphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,or5-Methyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,or a pharmaceutically acceptable salt thereof.
 18. The method of claim1, wherein the disease comprises alcoholic fatty liver disease (ALD) ora non-alcoholic fatty liver disease (NAFLD).
 19. The method of claim 1,wherein the disease is selected from the group consisting of simplefatty liver (steatosis), non-alcoholic steatohepatitis (NASH), andcirrhosis.
 20. The method of claim 1, wherein the disease isnon-alcoholic steatohepatitis (NASH).
 21. The method of claim 2, whereinthe one or more compounds are selected from the group consisting of:2,5-Dimethyl-N-(pyridin-2-yl)-1-(p-tolyl)-1H-pyrrole-3-carboxamide,2,5-Dimethyl-N-(pyrazin-2-yl)-1-(p-tolyl)-1H-pyrrole-3-carboxamide,2,5-Dimethyl-N-(4-phenylthiazol-2-yl)-1-(p-tolyl)-1H-pyrrole-3-carboxamide,N-Benzyl-2,5-dimethyl-1-(p-tolyl)-1H-pyrrole-3-carboxamide, and thepharmaceutically acceptable salts thereof.
 22. The method of claim 2,wherein the one or more compounds are selected from the group consistingof:5-Methyl-N-(pyridin-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(6-methylpyridin-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(pyridin-2-ylmethyl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(2-methyl-4-oxo-4H-chromen-7-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(3-methylisoxazol-5-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,N-(4,5-diphenylthiazol-2-yl)-5-methyl-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(1-methyl-1H-benzo[d]imidazol-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(quinolin-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(naphthalen-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,N-(benzo[d]thiazol-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(4-phenylthiazol-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,1-(2,3-Dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2,4-Dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(3-Chlorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Bromophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Cyanophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Methoxyphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(4-Fluoro-2-nitrophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Acetylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Carbamoylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-([1,1′-biphenyl]-2-yl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-1-(2-morpholinophenyl)-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-1-(naphthalen-1-yl)-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-fluorophenyl)-5-isopropyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,5-Ethyl-1-(2-fluorophenyl)-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,N-(6-bromoquinolin-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-(morpholinomethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-((4-methylpiperazin-1-yl)methyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-(pyrrolidin-1-ylmethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,N-(6-((diethylamino)methyl)quinolin-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-(piperidin-1-ylmethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,tert-butyl4-((2-(5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamido)quinolin-6-yl)methyl)piperazine-1-carboxylate,N-(6-((dimethylamino)methyl)quinolin-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-(thiomorpholinomethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-((4-morpholinopiperidin-1-yl)methyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,and5-methyl-N-(6-((4-(4-methylpiperazin-1-yl)piperidin-1-yl)methyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,and the pharmaceutically acceptable salts thereof.
 23. The method ofclaim 2, wherein the one or more compounds are selected from the groupconsisting of:5-Methyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-pyrazole-4-carboxamide,1-(2-Fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-Bromophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-Chlorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide1-(2-Ethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,6-dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(Tert-butyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,5-dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,4-difluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-methyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-cyclohexyl-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-methyl-1-(1-phenylethyl)-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-methyl-N-(quinolin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide,5-methyl-1-(3-methylpyridin-2-yl)-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(3-chloro-2-fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,6-difluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-bromo-6-fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-methyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-3-carboxamide,5-methyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-pyrazole-3-carboxamide,1-(2-ethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-3-carboxamide,1-phenyl-N-(quinolin-2-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxamide,1-phenyl-N-(quinolin-2-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide,3,5-dimethyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,5-dimethylphenyl)-3,5-dimethyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-bromophenyl)-3,5-dimethyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-ethyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-isopropyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-chloro-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-bromo-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-(dimethylamino)-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-ethylphenyl)-5-methyl-N-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide,1-(2-ethylphenyl)-N-(isoquinolin-3-yl)-5-methyl-1H-pyrazole-4-carboxamide,1-(2-ethylphenyl)-5-methyl-N-(quinolin-3-yl)-1H-pyrazole-4-carboxamide,1-(2-ethylphenyl)-5-methyl-N-(6-methylpyridin-2-yl)-1H-pyrazole-4-carboxamide,and the pharmaceutically acceptable salts thereof.
 24. The method ofclaim 2, wherein the one or more compounds are selected from the groupconsisting of:2,5-Dimethyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-imidazole-4-carboxamide,1-(2-Fluorophenyl)-2,5-dimethyl-N-(quinolin-2-yl)-1H-imidazole-4-carboxamide,1-(2-Bromophenyl)-2,5-dimethyl-N-(quinolin-2-yl)-1H-imidazole-4-carboxamide,2,5-Dimethyl-1-phenyl-N-(quinolin-2-yl)-1H-imidazole-4-carboxamide, andthe pharmaceutically acceptable salts thereof.
 25. The compound of claim12, wherein the compound is selected from the group consisting of:2,5-Dimethyl-N-(pyridin-2-yl)-1-(p-tolyl)-1H-pyrrole-3-carboxamide,2,5-Dimethyl-N-(pyrazin-2-yl)-1-(p-tolyl)-1H-pyrrole-3-carboxamide,2,5-Dimethyl-N-(4-phenylthiazol-2-yl)-1-(p-tolyl)-1H-pyrrole-3-carboxamide,N-Benzyl-2,5-dimethyl-1-(p-tolyl)-1H-pyrrole-3-carboxamide, and thepharmaceutically acceptable salts thereof.
 26. The compound of claim 12,wherein the compound is selected from the group consisting of:5-Methyl-N-(pyridin-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(6-methylpyridin-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(pyridin-2-ylmethyl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(2-methyl-4-oxo-4H-chromen-7-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(3-methylisoxazol-5-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,N-(4,5-diphenylthiazol-2-yl)-5-methyl-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(1-methyl-1H-benzo[d]imidazol-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(quinolin-2-yl)-1-(p-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(naphthalen-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,N-(benzo[d]thiazol-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-N-(4-phenylthiazol-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,1-(2,3-Dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2,4-Dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(3-Chlorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Bromophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Cyanophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Methoxyphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(4-Fluoro-2-nitrophenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Acetylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-Carbamoylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-([1,1′-biphenyl]-2-yl)-5-methyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-1-(2-morpholinophenyl)-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,5-Methyl-1-(naphthalen-1-yl)-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,1-(2-fluorophenyl)-5-isopropyl-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,5-Ethyl-1-(2-fluorophenyl)-N-(quinolin-2-yl)-1H-1,2,3-triazole-4-carboxamide,N-(6-bromoquinolin-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-(morpholinomethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-((4-methylpiperazin-1-yl)methyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-(pyrrolidin-1-ylmethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,N-(6-((diethylamino)methyl)quinolin-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-(piperidin-1-ylmethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,tert-butyl4-((2-(5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamido)quinolin-6-yl)methyl)piperazine-1-carboxylate,N-(6-((dimethylamino)methyl)quinolin-2-yl)-5-methyl-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-(thiomorpholinomethyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,5-methyl-N-(6-((4-morpholinopiperidin-1-yl)methyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,and5-methyl-N-(6-((4-(4-methylpiperazin-1-yl)piperidin-1-yl)methyl)quinolin-2-yl)-1-(o-tolyl)-1H-1,2,3-triazole-4-carboxamide,and the pharmaceutically acceptable salts thereof.
 27. The compound ofclaim 12, wherein the compound is selected from the group consisting of:5-Methyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-pyrazole-4-carboxamide,1-(2-Fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-Bromophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-Chlorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide1-(2-Ethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,6-dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(Tert-butyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,5-dimethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,4-difluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-methyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-cyclohexyl-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-methyl-1-(1-phenylethyl)-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-methyl-N-(quinolin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide,5-methyl-1-(3-methylpyridin-2-yl)-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(3-chloro-2-fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,6-difluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-bromo-6-fluorophenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-methyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-3-carboxamide,5-methyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-pyrazole-3-carboxamide,1-(2-ethylphenyl)-5-methyl-N-(quinolin-2-yl)-1H-pyrazole-3-carboxamide,1-phenyl-N-(quinolin-2-yl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxamide,1-phenyl-N-(quinolin-2-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide,3,5-dimethyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2,5-dimethylphenyl)-3,5-dimethyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-bromophenyl)-3,5-dimethyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-ethyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-isopropyl-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-chloro-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-bromo-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,5-(dimethylamino)-1-phenyl-N-(quinolin-2-yl)-1H-pyrazole-4-carboxamide,1-(2-ethylphenyl)-5-methyl-N-(naphthalen-2-yl)-1H-pyrazole-4-carboxamide,1-(2-ethylphenyl)-N-(isoquinolin-3-yl)-5-methyl-1H-pyrazole-4-carboxamide,1-(2-ethylphenyl)-5-methyl-N-(quinolin-3-yl)-1H-pyrazole-4-carboxamide,1-(2-ethylphenyl)-5-methyl-N-(6-methylpyridin-2-yl)-1H-pyrazole-4-carboxamide,and the pharmaceutically acceptable salts thereof.
 28. The compound ofclaim 12, wherein the compound is selected from the group consisting of:2,5-Dimethyl-N-(quinolin-2-yl)-1-(o-tolyl)-1H-imidazole-4-carboxamide,1-(2-Fluorophenyl)-2,5-dimethyl-N-(quinolin-2-yl)-1H-imidazole-4-carboxamide,1-(2-Bromophenyl)-2,5-dimethyl-N-(quinolin-2-yl)-1H-imidazole-4-carboxamide,2,5-Dimethyl-1-phenyl-N-(quinolin-2-yl)-1H-imidazole-4-carboxamide, andthe pharmaceutically acceptable salts thereof.